Inhibitors of DUX4 Induction for Regulation of Muscle Function

ABSTRACT

Disclosed are methods and compositions for the treatment of facioscapulohumeral muscular dystrophy. In some cases, the methods and compositions involve the use of kinase inhibitors include Src, Syk, Abl, Tie, Flt, ErbB, Trk, PRKDC, and Yes families to repress DUX 4  expression in muscle cells. Further disclosed are methods and cell based assays for screening compounds for the treatment of facioscapulohumeral muscular dystrophy.

CROSS REFERENCE

This application is a divisional application of U.S. Ser. No. 16/753,247filed Apr. 2, 2020 which claims priority to PCT Application No.US2018/057856 filed 26 Oct. 2018, which claims priority to U.S.Provisional Application No. 62/578,362, filed 27 Oct. 2017, and to U.S.Provisional Application No. 62/676,177, filed 24 May 2018, each of whichare incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

Facioscapulohumeral dystrophy (FSHD) is a neuromuscular disease with aprevalence that could reach 1 in 8,000. It is typically characterized byprogressive asymmetric muscle weakness. Manifestation of the diseaseincludes both typical and asymmetric patterns of muscle involvement anddisease progression. Two forms of FSHD have been identified: FSHD1 andFSHD2. Although both forms may display identical clinical phenotypes, itis unclear whether their genetic and epigenetic origins overlap or aredistinct. To date, the exact nature of pathophysiology of FSHD has notbeen established. As a result, target or pathway-biased treatment forthis disease is not available.

Chromatin is a complex of macromolecules (including DNA, protein, andRNA) with functions that include the packaging of DNA into smallervolumes to fit into a cell nucleus, and the control of gene expression.Histones are a major protein component of chromatin and bind DNA intoprotein-DNA complexes called nucleosomes. Epigenetic modifications(e.g., methylation, acetylation, ubiquitination, neddylation,phosphorylation) of histones, DNA and other macromolecules as well asmultiple effector molecules may regulate chromatin compaction by causingthe loosening or condensing chromatin, thereby affecting the ability ofregulatory factors to access DNA.

SUMMARY OF THE INVENTION

The present disclosure provides methods and compositions for thetreatment of facioscapulohumeral muscular dystrophy (FSHD) and othermuscle disorders or diseases, particularly any disease or disorderassociated with upregulated DUX4 expression or activity. In some cases,the methods and compositions involve the use of modulators of specificsignaling pathways including Src, PRKDC (also known as DNA-PK), Tie,Abl, Fit, Trk, Yes. FAK kinase families to modulate DUX4 activity inmuscle cells (e.g., by inhibiting or repressing its transcriptionalactivity, inhibiting or repressing its expression, increasing thedegradation of DUX4, mRNA or protein, or any other mechanism thatresults in reduced DUX4 activity). Further disclosed herein are methodsand cell based assays for screening compounds for the treatment of FSHDand other disorders or diseases, particularly a disorder associated withdysregulated or upregulated DUX4 activity or expression. Also disclosedherein are methods and compositions for the treatment of FSHD and otherdisorders or diseases, particularly a disorder associated withdysregulated or upregulated DUX4 activity or expression

In some embodiments, this disclosure provides a method for modulatingDUX4 activity in a subject in need thereof comprising administering tothe subject in need thereof a composition comprising a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I):

-   -   wherein E1 is phenyl, and wherein the E1 ring is substituted        with one to three R16 moieties;    -   wherein A is selected from the group consisting of imidazolyl,        and pyrazolyl;    -   G1 is a heteroaryl taken from the group consisting of pyrrolyl,        furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,        tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyrazinyl, and        pyrimidinyl;    -   G4 is a heterocyclyl taken from the group consisting of        oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,        oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl,        tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,        thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl        S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,        tropanyl, and homotropanyl;    -   A ring is substituted at any substitutable position with one A1        moiety, wherein A1 is selected from the group consisting of;

-   -   and wherein the symbol (**) is the point of attachment to the A        ring of formula I;    -   and wherein — indicates either a saturated or unsaturated bond;    -   the A ring is optionally substituted with one or more R2        moieties;    -   X2 is a direct bond wherein E1 is directly linked to the NR3        group of formula I;    -   X3 is —O—;    -   V, V1, and V2 are each independently O or represent two        hydrogens attached to the methylene carbon to which the V, V1,        or V2 is attached;    -   each Z3 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C8carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl        moiety can be partially or fully fluorinated, cyano, hydroxyl,        methoxy, oxo, (R3)₂NC(O)—, (R4)₂NC(O)—, —N(R4)C(O)R8,        (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R₅, —N(R4)SO₂R8, —(CH₂)N(R3)₂,        —(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —N(R3)(CH2)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂,        —O(CH2)_(q)R5, —N(R3)(CH₂)_(q)R5, —C(O)R5, —C(O)R8, and nitro;    -   in the event that Z3 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl,        C1-C6alkoxyC₂-C₆alkyl, (R4)₂N—C₂-C₆alkyl,        (R4)₂N—C₂-C6alkylN(R4)-C₂-C₆alkyl,        (R4)₂N—C₂-C₆alkyl-O—C₂-C₆alkyl, (R4)₂NC(O)—C1-C6alkyl,        carboxyC1-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-,        —C₂-C₆alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO₂R8, —C(O)R8,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(q)O(CH₂)_(n)G1,        —(CH₂)_(q)O(CH₂)_(n)G4, —(CH₂)_(q)N(R3)(CH₂)_(n)G1,        —(CH₂)_(q)N(R3)(CH₂)_(n)G4, —(CH₂)_(q)NHC(O)(CH₂)_(n)R5,        —(CH₂)_(q)C(O)NH(CH₂)_(q)R₅, —(CH₂)_(q)C(O)R5,        —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5, —(CH₂)_(q)NR4(CH₂)_(q)R5, and        —(CH₂)_(q)O(CH₂)_(q)R5;    -   in the event that Z4 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z6 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        hydroxyl, hydroxyC1-C6alkyl, hydroxyC₂-C₆ branched alkyl,        C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC₂-C₆ branched        alkyl-, C₂-C₆ branched alkoxy-, C1-C6alkylthio-, (R3)₂N—,        —N(R3)C(O)R8, (R4)₂N—, —R5, —N(R4)C(O)R8, —N(R3)SO₂R6,        —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5, —SO₂NH(R4), halogen,        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully        or partially fluorinated, —O(CH₂)_(q)N(R4)₂,        —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)O—C1-C6alkyl,        —N(R₃)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, N(R3)(CH₂)_(q)R₅,        —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17, —(CH₂)_(n)R17, —R17,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,        —(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and        —(CH₂)_(n)N(R3)(CH2)_(n)G4;    -   each R2 is selected from the group consisting of Z3-substituted        aryl, Z3-substituted G1-, Z3-substituted G4-, C1-C6alkyl,        branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein        the alkyl group is fully or partially fluorinated;    -   wherein each R3 is independently and individually selected from        the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, and Z3-substituted phenyl;    -   each R4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-,        dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched        C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branched        C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂,        —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, C3-C7-carbocyclyl, hydroxyl        substituted C3-C7-carbocyclyl-, alkoxy substituted        C3-C7-carbocyclyl-, dihydroxyl substituted C3-C7-carbocyclyl-,        and —(CH₂)_(n)R17;    -   each R5 is independently and individually selected from the        group consisting of

-   -   and wherein the symbol (##) is the point of attachment of the R5        moiety;    -   each R6 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, G1, and G4;    -   each R7 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl-,        dihydroxyC₂-C₆alkyl-, C₂-C₆alkoxyC₂-C₆alkyl-, branched        C3-C7alkyl-, branched hydroxyC₂-C₆ alkyl-, branched        C₂-C₆alkoxyC₂-C₆alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(q)R5, —)CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,        C3-C7-carbocyclyl, hydroxyl substituted C3-C7-carbocyclyl-,        alkoxy substituted C3-C7-carbocyclyl-, dihydroxy substituted        C3-C7-carbocyclyl, and —(CH₂)_(n)R17;    -   each R8 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        fluoroC1-C6alkyl wherein the alkyl moiety is partially or fully        fluorinated, C3-C7-carbocyclyl, phenyl-, phenylC1-C6alkyl-, G1,        G1-C1-C6alkyl-, G4, G4-C1-C6alkyl-, OH, C1-C6alkoxy, N(R3)₂,        N(R4)₂, and R5;    -   each R9 is independently and individually selected from the        group consisting of H, F, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, phenyl-C1-C6alkyl-, —(CH₂)_(n)G1, and        —(CH₂)_(n)G4;    -   each R10 is independently and individually selected from the        group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂, OH,        C1-C6alkoxy, and —N(R4)₂;    -   each R14 is independently and respectively selected from the        group consisting of H, C1-C6alkyl, branched C3-C6alkyl, and        C3-C7-carbocyclyl;    -   R16 is independently and individually selected from the group        consisting of fluorine and methyl;    -   each R17 is taken from the group comprising phenyl, naphthyl,        pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,        isothiazolyl, imdazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,        oxetanyl, azctadinyl, tetrahydrofuranyl, oxazolinyl,        oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,        dioxalinyl, azepinyl, oxepinyl, and diazepinyl;    -   wherein R17 can be optionally substituted with an R3        substituent,    -   R19 is H or C1-C6 alkyl;    -   n is 0-6, p is 1-4, q is 2-6; r is 0 or 1; t is 1-3, and v is 1        or 2.

Another embodiment provides a method for modulating DUX4 activity in asubject in need thereof comprising administering to the subject in needthereof a composition comprising a compound, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (I), andfurther described by the structure of Formula (II):

-   -   wherein A is pyrazolyl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:

-   -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)pheny)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(pyridin-3-yloxy)phenyl)urea;    -   1-(3)-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea;    -   1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-cyclopentyl        -1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;        1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(methylcarbamoyl)pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol        -5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(isopropylamino)pyridin-4-yloxy)-3-methylphenyl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,        and    -   1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,or a pharmaceutically acceptable salt thereof.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity in a subject (e.g., directly or vicariously) in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 1.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 2.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 3.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 4.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 5. Another embodimentprovides the method for modulating DUX4 activity wherein the modulationof DUX4 activity is inhibition of DUX4 activity.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I):

-   -   wherein E1 is phenyl, and wherein the E1 ring is substituted        with one to three R¹⁶ moieties;    -   wherein A is selected from the group consisting of imidazolyl,        and pyrazolyl;    -   G1 is a heteroaryl taken from the group consisting of pyrrolyl,        furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,        tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and        pyrimidinyl,    -   G4 is a heterocyclyl taken from the group consisting of        oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,        oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl,        tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,        thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl        S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,        tropanyl, and homotropanyl;

A ring is substituted at any substitutable position with one A1 moiety,wherein A1 is selected from the group consisting of:

-   -   and wherein the symbol (**) is the point of attachment to the A        ring of formula I,    -   and wherein — indicates either a saturated or unsaturated bond;    -   the A ring is optionally substituted with one or more R2        moieties;    -   X2 is a direct bond wherein E1 is directly linked to the NR3        group of formula I;    -   X3 is —O—;    -   V, V1, and V2 are each independently O or represent two        hydrogens attached to the methylene carbon to which the V, V1,        or V2 is attached,    -   each Z3 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C8carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl        moiety can be partially or fully fluorinated, cyano, hydroxyl,        methoxy, oxo, (R3)₂NC(O)—, (R4)₂NC(O)—, —N(R4)C(O)R8,        (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R₅, —N(R4)SO₂R8, —(CH₂)N(R3)₂,        —(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —N(R3)(CH2)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂,        —O(CH2)_(q)R5, —N(R3)(CH₂)_(q)R5, —C(O)R5, —C(O)R8, and nitro;    -   in the event that Z3 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl,        C1-C6alkoxyC₂-C₆alkyl, (R4)₂N—C₂-C₆alkyl,        (R4)₂N—C₂-C6alkylN(R4)-C₂-C₆alkyl,        (R4)₂N—C₂-C₆alkyl-O—C₂-C₆alkyl, (R4)₂NC(O)—C1-C6alkyl,        carboxyC1-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-,        —C₂-C₆alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO₂R8, —C(O)R8,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(q)O(CH₂)_(n)G1,        —(CH₂)_(q)O(CH₂)_(n)G4, —(CH₂)_(q)N(R3)(CH₂)_(n)G1,        —(CH₂)_(q)N(R3)(CH₂)_(n)G4, —(CH₂)_(q)NHC(O)(CH₂)_(n)R5,        —(CH₂)_(q)C(O)NH(CH₂)_(q)R₅, —(CH₂)_(q)C(O)R5,        —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5, —(CH₂)_(q)NR4(CH₂)_(q)R5, and        —(CH₂)_(q)O(CH₂)_(q)R5;    -   in the event that Z4 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z6 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        hydroxyl, hydroxyC1-C6alkyl, hydroxyC₂-C₆ branched alkyl,        C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC₂-C₆ branched        alkyl-, C₂-C₆ branched alkoxy-, C1-C6alkylthio-, (R3)₂N—,        —N(R3)C(O)R8, (R4)₂N—, —R5, —N(R4)C(O)R8, —N(R3)SO₂R6,        —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5, —SO₂NH(R4), halogen,        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully        or partially fluorinated, —O(CH₂)_(q)N(R4)₂,        —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)O—C1-C6alkyl,        —N(R₃)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, N(R3)(CH₂)_(q)R₅,        —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17, —(CH₂)_(n)R17, —R17,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,        —(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and        —(CH₂)_(n)N(R3)(CH2)_(n)G4;    -   each R2 is selected from the group consisting of Z3-substituted        aryl, Z3-substituted G1-, Z3-substituted G4-, C1-C6alkyl,        branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein        the alkyl group is fully or partially fluorinated;    -   wherein each R3 is independently and individually selected from        the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, and Z3-substituted phenyl;    -   each R4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-,        dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched        C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branched        C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂,        —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, C3-C7-carbocyclyl, hydroxyl        substituted C3-C7, alkoxy substituted C3-C7-carbocyclyl-,        dihydroxyl substituted C3-C7-carbocyclyl-, and —(CH₂)_(n)R17;    -   each R5 is independently and individually selected from the        group consisting of

-   -   and wherein the symbol (##) is the point of attachment of the R5        moiety;    -   each R6 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, G1, and G4;    -   each R7 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl-,        dihydroxyC₂-C₆alkyl-, C₂-C₆alkoxyC₂-C₆alkyl-, branched        C3-C7alkyl-, branched hydroxyC₂-C₆ alkyl-, branched        C₂-C₆alkoxyC₂-C₆alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,        C3-C7-carbocyclyl, hydroxyl substituted C3-C7-carbocyclyl-,        alkoxy substituted C3-C7-carbocyclyl-, dihydroxy substituted        C3-C7-carbocyclyl, and —(CH₂)_(n)R17;    -   each R8 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        fluoroC1-C6alkyl wherein the alkyl moiety is partially or fully        fluorinated, C3-C7-carbocyclyl, phenyl-, phenylC1-C6alkyl-, G1,        G1-C1-C6alkyl-, G4, G4-C1-C6alkyl-, OH, C1-C6alkoxy, N(R3)₂,        N(R4)₂, and R5;    -   each R9 is independently and individually selected from the        group consisting of H, F, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, phenyl-C1-C6alkyl-, —(CH₂)_(n)G1, and        —(CH₂)_(n)G4;    -   each R10 is independently and individually selected from the        group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂, OH,        C1-C6alkoxy, and —N(R4)₂;    -   each R14 is independently and respectively selected from the        group consisting of H, C1-C6alkyl, branched C3-C6alkyl, and        C3-C7-carbocyclyl;    -   R16 is independently and individually selected from the group        consisting of fluorine and methyl;    -   each R17 is taken from the group comprising phenyl, naphthyl,        pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,        isothiazolyl, imdazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,        oxetanyl, azctadinyl, tetrahydrofuranyl, oxazolinyl,        oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,        dioxalinyl, azepinyl, oxepinyl, and diazepinyl;    -   wherein R17 can be optionally substituted with an R3        substituent,    -   R19 is H or C1-C6 alkyl;    -   n is 0-6, p is 1-4, q is 2-6; r is 0 or 1; t is 1-3, and v is 1        or 2.

Another embodiment provides a method for treating a musculardegenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I), and further described by the structure ofFormula (II):

wherein A is pyrazolyl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, selected fromthe group consisting of:

-   -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(pyridin-3-yloxy)phenyl)urea;    -   1-(3)-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea;    -   1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;        1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(methylcarbamoyl)pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol        -5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(isopropylamino)pyridin-4-yloxy)-3-methylphenyl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,        and    -   1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,or a pharmaceutically acceptable salt thereof.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 1.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 2.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 3.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 4.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 5.

Another embodiment proves the method of treating a muscular degenerativedisorder wherein the muscular degenerative disorder is selected fromfacioscapulohumeral muscular dystrophy (FSHD), facioscapulohumeralmuscular dystrophy-1 (FSHD1), facioscapulohumeral muscular dystrophy-2(FSHD2), Becker muscular dystrophy, Duchenne muscular dystrophy,myotonic dystrophies type 1, myotonic dystrophies types 2, nemalinemyopathy or spinal muscular atrophy. Another embodiment proves themethod wherein the subject is a human.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity in a subject in need thereof comprising administering tothe subject in need thereof a composition comprising a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (III):

wherein

-   -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   n is 0-5;    -   L¹ is absent or *—(CR^(a)R^(b))—C(═O)—, wherein * denotes        attachment point to the carbonyl carbon;        -   R^(a) and R^(b) are independently selected from hydrogen,            C₁-C₆alkyl, or C₁-C₆ haloalkyl;        -   or R^(a) and R^(b) are taken together with the carbon to            which they are attached to form a 3-, 4-, 5-, or 6-membered            cycloalkyl or a 3-, 4-, 5-, or 6-membered heterocycloalkyl;    -   each R² is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   or two R² on adjacent atoms are taken together with the atoms to        which they are attached to form an unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   m is 0-4;    -   L² is absent, —O—, —O—(C₁-C₄ alkylene)-, or —NR^(c)—C(═O)—;    -   each R^(c) is independently selected from hydrogen, C₁-C₆ alkyl,        or C₁-C₆ haloalkyl;    -   R³ is unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein when R³ is        substituted, it is substituted by 1-3 R⁴;        -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R²⁰, or R²¹ is substituted,        substituents on the R¹, R², R⁴, R²⁰, or R²¹ are independently        selected at each occurrence from halogen, —CN, —NO₂, —OR²²,        —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²NR²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;        -   each R²² is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl; <or two R²² groups            are taken together with the N atom to which they are            attached to form a N-containing heterocycle; and        -   each R²³ is independently selected from C₁-C₆alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (IV):

wherein

-   -   L is absent or —C₁-C₄ alkylene;    -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   or two R¹ on adjacent atoms are taken together with the atoms to        which they are attached to form a unsubstituted or substituted        carbocycle, or unsubstituted or substituted heterocycle; wherein        if the carbocycle or heterocycle is substituted, it is        substituted with 1-3 R⁷;        -   each R⁷ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R¹⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   n is 0-5;    -   R² and R⁴ are each independently hydrogen, or —NR⁵R⁶, or        unsubstituted or substituted heterocycle;        -   each R⁵ and R⁶ is independently hydrogen, unsubstituted or            substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆            alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,            unsubstituted or substituted cycloalkyl, unsubstituted or            substituted heterocycloalkyl, unsubstituted or substituted            aryl, unsubstituted or substituted heteroaryl, unsubstituted            or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or            substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted            or substituted —C₁-C₆-alkylene-aryl, or unsubstituted or            substituted —C₁-C₆-alkylene-heteroaryl;        -   or R⁵ and R⁶ are taken together with the N atom to which            they are attached to form an unsubstituted or substituted            N-containing heterocycle;    -   R³ is hydrogen, halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R² and R³ are taken together with the atoms to which they are        attached to form a unsubstituted or substituted carbocycle, or        unsubstituted or substituted heterocycle; wherein if the        carbocycle or heterocycle is substituted, it is substituted with        1-3 R⁸;        -   each R⁸ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;        -   or two R⁷ on the same carbon atom are taken together to form            a C═O, or C═S;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or R²¹is        substituted, substituents on the R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or        R²¹are independently selected at each occurrence from halogen,        —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²²,        —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³,        —SO₂NR²²R²², —NR²²SO₂R²³, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        monocyclic cycloalkyl, monocyclic heterocycloalkyl, phenyl,        benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆alkyl,            C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, phenyl, benzyl,            5-membered heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³ is independently selected from C₁-C₆alkyl, C₁-C₆            hydroxyalkyl, C₁-C₆alkyl C₃-C₆ cycloalkyl, phenyl, benzyl,            5-membered heteroaryl, and 6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (V):

-   -   wherein    -   X¹ is N or CR¹;        -   R¹ is hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   X² is N or CR²;        -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   X³ is N or CR³;        -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   X⁴ is N or CR⁴;        -   R⁴ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl;    -   wherein 0, 1, or 2 of X¹, X², X³, and X⁴ are N;    -   R⁵ is hydrogen, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;        -   wherein if R⁵ is substituted, it is substituted with 1-3 R⁹;        -   each R⁹ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO², —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR₂₁C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl;    -   R⁶ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R⁵ and R⁶ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹³;        -   each R¹³ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   R⁷ is hydrogen, unsubstituted or substituted cycloalkyl,        unsubstituted or substituted heterocycloalkyl, unsubstituted or        substituted aryl, unsubstituted or substituted heteroaryl,        unsubstituted or substituted —C₁-C₆-alkylene-cycloalkyl, or        —C(═O)R¹¹;        -   R¹¹ unsubstituted phenyl, or phenyl substituted by 1-3 R¹²,            -   each R¹² is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —0C(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalky, unsubstituted or substituted aryl,                unsubstituted or substituted heteroaryl, unsubstituted                or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted                or substituted —C₁-C₆-alkylene-heterocycloalklyl,                unsubstituted or substituted —C₁-C₆-alkylene-aryl, or                unsubstituted or substituted —C₁-C₆-alkylene-heteroaryl;    -   R⁸ is hydrogen, C₁-C₆alkyl or C₁-C₆ haloalkyl;    -   or R⁷ and R⁸ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹⁰;        -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R₂₀ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R², R³, R⁴, R⁷, R⁹, R¹⁰, R¹², R¹³, R²⁰, or        R²¹is substituted, substituents on the R², R³, R⁴, R⁷, R⁹, R¹⁰,        R¹², R¹³, R²⁰, or R²¹are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —C(═O)NR²²R²², —C(═O)NR²²—OR²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, monocyclic heterocycloalkyl substituted with a        R²³, phenyl, benzyl, 5-membered heteroaryl, and 6-membered        heteroaryl; or two substituents on the same carbon atom are        taken together to form a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³is independently selected from C₁-C₆ alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (VI):

wherein:

-   -   X¹ and X² are independently N or CH;    -   X³ is N or CR³;        -   R³ is hydrogen, —CN, or -L-Ar,    -   X⁴ is N or CR⁴;        -   R⁴ is hydrogen, or -L-Ar;    -   wherein one of X³ and X⁴ is C-L-Ar;        -   L is —NH—, —O—, —S—, —C₁-C₂ alkylene-, or            -heterocycloalkylene-C(═O)—;        -   Ar is substituted or unsubstituted phenyl or substituted or            unsubstituted 5- or 6-membered heteroaryl; wherein when Ar            is substituted, it is substituted with 1-3 R⁶;            -   each R⁶ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)²NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —(C₁-C₄                alkylene)-C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl, or                unsubstituted or substituted heteroaryl;            -   or two R⁶ on adjacent atoms are taken together with the                atoms to which they are attached to form an                unsubstituted or substituted cycloalkyl, unsubstituted                or substituted heterocycloalkyl, unsubstituted or                substituted aryl, or unsubstituted or substituted                heteroaryl;    -   each R⁵ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁵, R⁶, R²⁰, or R²¹is substituted, substituents        on the R⁵, R⁶, R²⁰, or R²¹are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —OC(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;        -   each R²² is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²² groups are taken together with the N atom to            which they are attached to form a N-containing heterocycle;            and        -   each R²³ is independently selected from C₁-C₆alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (VII):

wherein:

-   -   X¹ is —S—, —O—, or —NR¹—;        -   R¹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,            unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or            substituted C₂-C₆ alkynyl, unsubstituted or substituted            cycloalkyl, unsubstituted or substituted heterocycloalkyl,            unsubstituted or substituted aryl, or unsubstituted or            substituted heteroaryl; wherein when R¹ is substituted, it            is substituted by 1-3 R⁷;        -   each R⁷ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²¹, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted cycloalkyl, unsubstituted or substituted            heterocycloalkyl, unsubstituted or substituted aryl, or            unsubstituted or substituted heteroaryl;    -   X² is N or CR²;        -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl; wherein when R² is substituted, it is            substituted by 1-3 R⁸;        -   each R⁸ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted cycloalkyl, unsubstituted or substituted            heterocycloalkyl, unsubstituted or substituted aryl, or            unsubstituted or substituted heteroaryl;    -   X³ is N or CR³; wherein X² and X³ are not both N;        -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl, unsubstituted or substituted            —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted            —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or            substituted —C₁-C₆-alkylene-aryl, or unsubstituted or            substituted —C₁-C₆-alkylene-heteroaryl; wherein when R³ is            substituted, it is substituted by 1-3 R⁹;            -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)₂R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl,                unsubstituted or substituted heteroaryl, unsubstituted                or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted                or substituted —C₁-C₆-alkylene-heterocycloalkyl,                unsubstituted or substituted —C₁-C₆-alkylene-aryl, or                unsubstituted or substituted —C₁-C₆-alkylene-heteroaryl;    -   Ar is a 6-membered aromatic ring comprising 0-2 nitrogen atoms;    -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR⁵, —SH,        —SR⁵, —NO₂, —NR⁶R⁶, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)R⁵,        —S(═O)₂NR⁶R⁶, —C(═O)R⁵, —OC(═O)R⁵, —C(═O)OR⁶, —OC(═O)OR⁶,        —C(═O)NR⁶R⁶, —OC(═O)NR⁶R⁶, —NR⁶C(═O)NR⁶R⁶, —NR⁶C(═O)R⁵,        —NR⁶C(═O)OR⁶, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl, unsubstituted or substituted        —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-aryl, or unsubstituted or substituted        —C₁-C₆-alkylene-heteroaryl;        -   each R⁵ is independently selected from unsubstituted or            substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆            alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,            unsubstituted or substituted cycloalkyl, unsubstituted or            substituted heterocycloalkyl, unsubstituted or substituted            aryl, or unsubstituted or substituted heteroaryl; wherein if            R⁵ is substituted, it is substituted by 1-3 R¹⁰;            -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl, or                unsubstituted or substituted heteroaryl;        -   each R⁶is independently selected from hydrogen,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₁-C₆ alkenyl, unsubstituted or substituted            C₁-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl; wherein if R⁶ is substituted, it is substituted            by 1-3 R¹¹;        -   each R¹¹ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰, or R²¹is        substituted, substituents on the R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰,        or R²¹are independently selected at each occurrence from        halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²²,        —NR²²R²², —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³,        —SO₂R²³, —SO₂NR²²R²², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, benzyl substituted with        phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;    -   each R²²is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl. benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²²groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³is independently selected from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (III):

wherein

-   -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   n is 0-5;    -   L¹ is absent or *—(CR^(a)R^(b))—C(═O)—, wherein * denotes        attachment point to the carbonyl carbon;        -   R^(a) and R^(b) are independently selected from hydrogen,            C₁-C₆alkyl, or C₁-C₆ haloalkyl;        -   or R^(a) and R^(b) are taken together with the carbon to            which they are attached to form a 3-, 4-, 5-, or 6-membered            cycloalkyl or a 3-, 4-, 5-, or 6-membered heterocycloalkyl;    -   each R² is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   or two R² on adjacent atoms are taken together with the atoms to        which they are attached to form an unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   m is 0-4;    -   L² is absent, —O—, —O—(C₁-C₄ alkylene)-, or —NR^(c)—C(═O)—;    -   each R^(c) is independently selected from hydrogen, C₁-C₆ alkyl,        or C₁-C₆ haloalkyl;    -   R³ is unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein when R³ is        substituted, it is substituted by 1-3 R⁴;        -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R²⁰, or R²¹ is substituted,        substituents on the R¹, R², R⁴, R²⁰, or R²¹ are independently        selected at each occurrence from halogen, —CN, —NO₂, —OR²²,        —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²NR²³, C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;    -   each R²² is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²² groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³ is independently selected from C₁-C₆alkyl, C₃-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (IV):

wherein

-   -   L is absent or —C₁-C₄ alkylene;    -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   or two R¹ on adjacent atoms are taken together with the atoms to        which they are attached to form a unsubstituted or substituted        carbocycle, or unsubstituted or substituted heterocycle; wherein        if the carbocycle or heterocycle is substituted, it is        substituted with 1-3 R⁷;        -   each R⁷ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R¹⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   n is 0-5;    -   R² and R⁴ are each independently hydrogen, or —NR⁵R⁶, or        unsubstituted or substituted heterocycle;        -   each R⁵ and R⁶ is independently hydrogen, unsubstituted or            substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆            alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,            unsubstituted or substituted cycloalkyl, unsubstituted or            substituted heterocycloalkyl, unsubstituted or substituted            aryl, unsubstituted or substituted heteroaryl, unsubstituted            or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or            substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted            or substituted —C₁-C₆-alkylene-aryl, or unsubstituted or            substituted —C₁-C₆-alkylene-heteroaryl;        -   or R⁵ and R⁶ are taken together with the N atom to which            they are attached to form an unsubstituted or substituted            N-containing heterocycle;    -   R³ is hydrogen, halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R² and R³ are taken together with the atoms to which they are        attached to form a unsubstituted or substituted carbocycle, or        unsubstituted or substituted heterocycle; wherein if the        carbocycle or heterocycle is substituted, it is substituted with        1-3 R⁸;        -   each R⁸ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;        -   or two R⁷ on the same carbon atom are taken together to form            a C═O, or C═S;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or R²¹is        substituted, substituents on the R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or        R²¹are independently selected at each occurrence from halogen,        —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²²,        —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³,        —SO₂NR²²R²², —NR²²SO₂R²³, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        monocyclic cycloalkyl, monocyclic heterocycloalkyl, phenyl,        benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆alkyl,            C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, phenyl, benzyl,            5-membered heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³ is independently selected from C₁-C₆alkyl, C₁-C₆            hydroxyalkyl, C₁-C₆alkyl C₃-C₆ cycloalkyl, phenyl, benzyl,            5-membered heteroaryl, and 6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, havng thestructure of Formula (V)

-   -   wherein    -   X¹ is N or CR¹;        -   R¹ is hydrogen, halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl;    -   X² is N or CR₂;        -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═OX)R²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   X³ is N or CR³;        -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O),NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   X⁴ is N or CR⁴;        -   R⁴ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl;    -   wherein 0, 1, or 2 of X¹, X², X³, and X⁴ are N;    -   R⁵ is hydrogen, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;        -   wherein if R⁵ is substituted, it is substituted with 1-3 R⁹;        -   each R⁹ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl;    -   R⁶ is hydrogen, C₁-C₆alkyl or C₁-C₆ haloalkyl;    -   or R⁵ and R⁶are taken together with the N atom to which they are        attached to form an unsubstituted or substituted N-containing        heterocycle; wherein if the heterocycle is substituted, it is        substituted by 1-3 R¹³;        -   each R¹³ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   R⁷ is hydrogen, unsubstituted or substituted cycloalkyl,        unsubstituted or substituted heterocycloalkyl, unsubstituted or        substituted aryl, unsubstituted or substituted heteroaryl,        unsubstituted or substituted —C₁-C₆-alkylene-cycloalkyl, or        —C(═O)R¹¹;        -   R¹¹ unsubstituted phenyl, or phenyl substituted by 1-3 R¹²;            -   each R¹² is independently halogen, —CN, —H, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl,                unsubstituted or substituted heteroaryl, unsubstituted                or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted                or substituted —C₁-C₆-alkylene-heterocycloalkyl,                unsubstituted or substituted —C₁-C₆-alkylene-aryl, or                unsubstituted or substituted —C₁-C₆-alkylene-heteroaryl;    -   R⁸ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R⁷ and R⁸ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹⁰;        -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R²⁰ is independently selected from unsubstituted or        substituted C1-C6alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R², R³, R⁴, R⁷, R⁹, R¹⁰, R¹², R¹³, R²⁰, or        R²¹is substituted, substituents on the R², R³, R⁴, R⁷, R⁹, R¹⁰,        R¹², R¹³, R²⁰, or R²¹are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —C(═O)NR²²R²², —C(═O)NR²²—OR²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²²,        C₁-C₆alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, monocyclic heterocycloalkyl substituted with a        R²³, phenyl, benzyl, 5-membered heteroaryl, and 6-membered        heteroaryl; or two substituents on the same carbon atom are        taken together to form a C═O or C═S;        -   each R²² is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²² groups are taken together with the N atom to            which they are attached to form a N-containing heterocycle;            and        -   each R²³ is independently selected from C₁-C₆ alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (VI):

wherein:

-   -   X¹ and X² are independently N or CH;    -   X³ is N or CR³;        -   R³ is hydrogen, —CN, or -L-Ar,    -   X⁴ is N or CR⁴;        -   R⁴ is hydrogen, or -L-Ar;    -   wherein one of X³ and X⁴ is C-L-Ar;        -   L is —NH—, —O—, —S—, —C₁-C₂ alkylene-, or            -heterocycloalkylene-C(═O)—;        -   Ar is substituted or unsubstituted phenyl or substituted or            unsubstituted 5- or 6-membered heteroaryl; wherein when Ar            is substituted, it is substituted with 1-3 R⁶;        -   each R⁶ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)²NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —(C₁-C₄            alkylene)-C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,            —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted            C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,            unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or            substituted cycloalkyl, unsubstituted or substituted            heterocycloalkyl, unsubstituted or substituted aryl, or            unsubstituted or substituted heteroaryl;        -   or two R⁶ on adjacent atoms are taken together with the            atoms to which they are attached to form an unsubstituted or            substituted cycloalkyl, unsubstituted or substituted            heterocycloalkyl, unsubstituted or substituted aryl, or            unsubstituted or substituted heteroaryl;    -   each R⁵ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁵, R⁶, R²⁰, or R²¹is substituted, substituents        on the R⁵, R⁶, R²⁰, or R²¹ are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —OC(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;        -   each R²² is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²² groups are taken together with the N atom to            which they are attached to form a N-containing heterocycle;            and        -   each R²³ is independently selected from C₁-C₆alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (VII):

wherein:

-   -   X¹ is —S—, —O—, or —NR¹—;        -   R¹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,            unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or            substituted C₂-C₆ alkynyl, unsubstituted or substituted            cycloalkyl, unsubstituted or substituted heterocycloalkyl,            unsubstituted or substituted aryl, or unsubstituted or            substituted heteroaryl, wherein when R1 is substituted, it            is substituted by 1-3 R⁷;            -   each R⁷ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl, or                unsubstituted or substituted heteroaryl;    -   X² is N or CR²;        -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl; wherein when R² is substituted, it is            substituted by 1-3 R⁸;            -   each R⁸ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆alkyl, unsubstituted                or substituted cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl, or                unsubstituted or substituted heteroaryl;    -   X³ is N or CR³; wherein X² and X³ are not both N;        -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl, unsubstituted or substituted            —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted            —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or            substituted —C₁-C₆-alkylene-aryl, or unsubstituted or            substituted —C₁-C₆-alkylene-heteroaryl; wherein when R3 is            substituted, it is substituted by 1-3 R⁹;            -   each R⁹ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl,                unsubstituted or substituted heteroaryl, unsubstituted                or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted                or substituted —C₁-C₆-alkylene-heterocycloalkyl,                unsubstituted or substituted —C₁-C₆-alkylene-aryl, or                unsubstituted or substituted —C₁-C₆-alkylene-heteroaryl,    -   Ar is a 6-membered aromatic ring comprising 0-2 nitrogen atoms;    -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR⁵, —SH,        —SR⁵, —NO₂, —NR⁶R⁶, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)R⁵,        —S(═O)₂NR⁶R⁶, —C(═O)R⁵, —OC(═O)R⁵, —C(═O)OR⁶, —OC(═O)OR⁶,        —C(═O)NR⁶R⁶, —OC(═O)NR⁶R⁶, —NR⁶C(═O)NR⁶R⁶, —NR⁶C(═O)R⁵,        —NR⁶C(═O)OR⁶, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl, unsubstituted or substituted        —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-aryl, or unsubstituted or substituted        —C₁-C₆-alkylene-heteroaryl;        -   each R⁵ is independently selected from unsubstituted or            substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆            alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,            unsubstituted or substituted cycloalkyl, unsubstituted or            substituted heterocycloalkyl, unsubstituted or substituted            aryl, or unsubstituted or substituted heteroaryl; wherein if        -   R⁵ is substituted, it is substituted by 1-3 R¹⁰;        -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R⁶is independently selected from hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein if R⁶is        substituted, it is substituted by 1-3 R¹¹;        -   each R¹¹ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   n is 0-4;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆ alkylene-heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰, or R²¹ is        substituted, substituents on the R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰,        or R²¹ are independently selected at each occurrence from        halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²²,        —NR²²R²², —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³,        —SO₂R²³, —SO₂NR²²R²², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, benzyl substituted with        phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²² groups are taken together with the N atom to            which they are attached to form a N-containing heterocycle;            and        -   each R²³ is independently selected from C₁-C₆ alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 18 or 19.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 20 or 21.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity in a subject in need thereof comprising administering tothe subject in need thereof a composition comprising a compound, or apharmaceutically acceptable salt thereof, selected from a compoundprovided in FIG. 22 or 23.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 24 or 25.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 26 or 27.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 28 or 29. Anotherembodiment provides a method for modulating DUX4 activity wherein themodulation of DUX4 activity is inhibition of DUX4 activity.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 18 or19.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 20 or21.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 22 or23.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 24 or25.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 26 or27.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 28 or29.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder wherein the muscular degenerativedisorder is selected from facioscapulohumeral muscular dystrophy (FSHD),facioscapulohumeral muscular dystrophy-1 (FSHD1), facioscapulohumeralmuscular dystrophy-2 (FSHD2). Becker muscular dystrophy, Duchennemuscular dystrophy, myotonic dystrophies type 1, myotonic dystrophiestypes 2, nemaline myopathy, spinal muscular atrophy, congenital myotonicdystrophy, congenital muscular dystrophies, LAMA2, SEPN1, GNEmyopathies, and SMARD1.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, wherein thesubject is a human.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, orcompound according to any one of formulas I-VII, or a salt thereof),wherein the modulating DUX4 activity comprises reducing expression ofDUX4.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, orcompound according to any one of formulas I-VII, or a salt thereof),wherein the reduction of DUX4 expression occurs at the mRNA level.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the reduction of DUX4 expression occurs at the protein level.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the subject has upregulated DUX4 expression or activity prior toadministration of the compound.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the method further comprises detecting activity or expression ofDUX4 in the subject prior to, following, or both prior to and followingadministration of the compound.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the method further comprises monitoring DUX4 expression oractivity in a tissue of the subject following administration of thecompound In some embodiments, DUX4 expression is monitored by monitoringDUX4 mRNA expression, DUX4 protein expression, or both DUX4 mRNAexpression and DUX4 protein expression. In some embodiments, the methodcomprises taking a blood, plasma, serum or urine sample from the subjectand detecting the level of a marker of muscle injury. In someembodiments, the method comprises taking a blood, plasma, serum or urinesample from the subject and detecting the level of creatinine kinase,aldolase, and/or muscle enzymes in the sample. In some embodiments, themethod comprises monitoring the level of DUX4, creatinine kinase,aldolase, or muscle enzymes or any combination thereof over time, suchas over two time points, over three time points. In cases where a markerof muscle injury increases or stays the same, the level of compoundadministered to the subject may, in some embodiments, be adjustedupwards. In uses where the marker decreases over time, the level of thecompound administered to the subject may, in some embodiments, bemaintained or adjusted downward. In some embodiments, provided herein isa method of treating a muscular degenerative disorder in a subject inneed thereof or modulating DUX4 activity in a subject in need there ofusing any of the compounds described herein (e.g. rebastinib, or a saltthereof, or a compound according to any one of formulas I-VII, or a saltthereof), wherein, following administration of the compound, the subjectin need thereof experiences a least a 10%, at least a 25%, at least a50%, at least a 75%, or at least a 100% decrease in a marker of muscleinjury, a muscle enzyme, creatinine kinase, and/or aldolase, or anycombination thereof.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the method further comprises detecting activity or expression ofa DUX4 target gene prior to, following, or both prior to and followingadministration of the compound. In some embodiments, wherein the DUX4target gene is one or more genes selected from the group consisting ofCCNA1, KHDC1L, LEUTX, M8D3L2, PRAMEF2, PRAMEF6, SPRYD5, TRLM43, TRIM49,ZNF296, and ZSCAN4.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein, following administration of the compound, the subject in needthereof experiences a least a 10%, at least a 25%, at least a 50%, atleast a 75%, or at least 100% decrease in DUX4 expression or activity.In some embodiments, the decrease in DUX4 expression or activity occursin muscle tissue, or observed in a muscle biopsy In some cases, thedecrease occurs in a blood, serum, plasma, or urine sample and maydetected by sampling blood, scrum, plasma or urine.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the method further comprises conducting a muscle or tissuebiopsy on the subject in need thereof.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt or analogthereof, or a compound according to any one formulas I-VII, or a saltthereof), wherein the muscle or tissue biopsy is assessed for DUX4expression or activity. In some embodiments, the method comprisesmonitoring the level or activity of DUX4 in the subject over time,following administration of the compound In some embodiments, the levelor activity of DUX4 is monitored in one or more tissues such as blood,serum, plasma, muscle tissue, or other tissue. In some embodiments, thelevel or activity of DUX4 is monitored in a particular cell type such asmulti-nucleated cell, myoblast, or myotube.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the method further comprises monitoring a level of the compoundin the subject over time.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the method further comprises monitoring a level of the compoundin blood, serum, plasma, tissue, or muscle tissue of the subject in needthereof.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered orally, intramuscularly, ortransdermally to the subject in need thereof. In some embodiments, thecompound is administered orally.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g., rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered orally to the subject in needthereof and wherein a concentration of the compound is measured inmuscle tissue of the subject.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered orally to the subject in needthereof and wherein DUX4 expression or activity is measured in muscletissue of the subject.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered at a daily dose of less than 100mg, a daily dose of less than 90 mg, or a daily dose of less than 80 mg.In some embodiments, the daily dose is less than 100 mg.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered at a daily dose of between 50-60mg/m². In some embodiments, the daily dose is between 10-80 mg/m².

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered for over 28 contiguous days.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered to the subject in need thereof atleast once every other day over a period of at least 28 days.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound is administered to the subject in need thereof atleast once every other day over a period of at least 1 month, 2 months,6 months, 1 year, 2 years, or 5 years

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound comprises rebastinib,4-(4-(3-(3-(tert-butyl)-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureido)-2-methylphenoxy)-N-methylpicolinamide,or4-(4-(3-(3-(tert-butyl)-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)ureido)-3-fluorophenoxy)-N-methylpicolinamide.In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound comprises rebastinib.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound comprises4-(4-(3-(3-(tert-butyl)-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureido)-2-methylphenoxy)-N-methylpicolinamide.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according to any one of formulas I-VII, or a salt thereof),wherein the compound comprises4-(4-(3-(3-(tert-butyl)-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)ureido)-3-fluorophenoxy)-N-methylpicolinamide.

In some embodiments, this disclosure provides a method of treatingfacioscapulohumeral muscular dystrophy (FSHD) in a subject in needthereof, comprising administering a SRC kinase inhibitor to a subjecthaving FSHD. In some embodiments, this disclosure provides a method oftreating facioscapulohumeral muscular dystrophy (FSHD) comprisingadministering a PRKDC kinase inhibitor and/or a Src kinase inhibitor toa subject having a muscle deficiency or disorder or a disorderassociated with upregulated DUX4 expression or activity.

In some embodiments, this disclosure provides a method of treatingfacioscapulohumeral muscular dystrophy (FSHD) comprising administering aPRKDC kinase inhibitor to a subject having FSHD or to as subject with adisease or disorder associated with upregulated DUX4 expression. In someembodiments, the method further comprises administering a SRC kinaseinhibitor to the subject having FSHD. In some embodiments, the methodfurther comprises (a) administering a compound that functions as both aPRKDC inhibitor and as a SRC inhibitor to the subject having FSHD or (b)administering two separate compounds to the subject having FSHD whereinone of the separate compounds is a PRKDC inhibitor and the otherseparate compound is a SRC inhibitor.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference in their entiretiesand to the same extent as if each individual publication, patent, orpatent application was specifically and individually indicated to beincorporated by reference

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 provides the structures of compounds for modulating DUX4activity.

FIG. 2 provides the structures of compounds for modulating DUX4activity.

FIG. 3 provides the structures of compounds for modulating DUX4activity.

FIG. 4 provides the structures of compounds for modulating DUX4activity.

FIG. 5 provides the structures of compounds for modulating DUX4activity.

FIG. 6 provides the workflow for hESC-SkM assays.

FIG. 7 FSHD hESC-SkM Primary Screen for GBC0905 (Rebastinib, DCC-2036).100 nM GBC0905 treatment of FSHD hESC-SkM results in decreased DUX4expression with no significant off-target toxicity as evidenced bymyonuclear count or Myosin Heavy Chain area while a positive controlGBC0772 (MLN4924) inhibits myogenesis and leads to a non-specificdecrease in DUX4 and Myosin Heavy Chain expression.

FIG. 8A and FIG. 8B FSHD hESC-SkM Dose Curve: GBC0905 (Rebastinib.DCC-2036) treatment of FSHD hESC-SkM results in decreased DUX4expression in a dose-dependent manner. In contrast, treatment withmyogenesis inhibitor GBC0772 (M1.N4924) decreases DUX4 and Myosin HeavyChain Area equipotently, showing non-specific effect

FIG. 9 provides representative images from the dose response experimentof GBC0905 (Rebastinib, DCC-2036)

FIG. 10 provides the workflow for assays with primary patientbiopsy-derived muscle.

FIG. 11 A, FIG. 11B, FIG. 11C, FIG. 11D FSHD Primary Patient BiopsyMyotube Dose Curve: GBC0905 (Rebastinib, DCC-2036) treatment of FSHDprimary patient biopsy muscle cultures reduces clinically relevant DUX4and H3.X/Y stress marker expression in a dose-dependent manner withoutyielding a toxic or myogenic inhibitory effect.

FIG. 12 and FIG. 13 Representative images from the dose response studiesof GBC0905 (Rebastinib, DCC-2036) in FSHD primary patient biopsymyotubes

FIGS. 14A and 14B FSHD Primary Patient Biopsy Myotube Dose Curve:Inhibition of Caspases 3/7 mediated apoptosis. GBC0905 rescues FSHDpatient-derived myotubes from DUX4-induced death by Caspase 3/7-mediatedapoptosis.

FIGS. 15A and 15B FSHD Primary Patient Biopsy Myotube Dose Curve-GBC0905(Rebastinib, DCC-2036) rescues DUX4-mediated cell death in a doseresponse manner.

FIG. 16 provides representative images for GBC0905 (Rebastinib,DCC-2036)-mediated protection of FSHD affected primary patient biopsymyotubes at 3 concentration points

FIGS. 17A and 17B FSHD Primary Patient Biopsy Myotube Dose Curve—DUX4Target Gene and Myogenic Gene Expression. GBC0905 (Rebastinib, DCC-2036)treatment induces a concentration-dependent reduction of a suite ofreported DUX4 target genes with no negative effect on myogenic geneexpression.

FIG. 18 provides the structures of compounds for modulating DUX4activity.

FIG. 19 provides the structures of compounds for modulating DUX4activity.

FIG. 20 provides the structures of compounds for modulating DUX4activity.

FIG. 21 provides the structures of compounds for modulating DUX4activity.

FIG. 22 provides the structures of compounds for modulating DUX4activity.

FIG. 23 provides the structures of compounds for modulating DUX4activity.

FIG. 24 provides the structures of compounds for modulating DUX4activity.

FIG. 25 provides the structures of compounds for modulating DUX4activity.

FIG. 26 provides the structures of compounds for modulating DUX4activity.

FIG. 27 provides the structures of compounds for modulating DUX4activity

FIG. 28 provides the structures of compounds for modulating DUX4activity.

FIG. 29 provides the structures of compounds for modulating DUX4activity.

FIG. 30 provides mean plasma rebistinib concentration-time profilefollowing a single administration of rebastinib by eitherintraperitoneal (IP) or intramuscular injection (IM).

FIGS. 31A and 31B provides mean brain and muscle rebastinibconcentration-time profile following a single administration ofrebistinib by either intraperitoncal (IP) or intramuscular injection(IM).

FIGS. 32A and 32B illustrates DNA methylation levels in hESC-derivedmyotubes at the 4qA and D4Z4 regions on chromosome L correlate with FHSDdisease.

FIGS. 33A and FIG. 33B illustrates GBC0905 does not modify DNAmethylation levels in FHSD-affected myotubes at the 4qA or D4Z4 regionsof chromosome 4.

FIGS. 34A and FIG. 34B illustrate knockdown of GBC0905 target kinasessuch as PRKDC and SRC inhibits DUX4 and H3.X/Y expression without celltoxicity or myogenic inhibition effects in FSHD-affected myotubes.

FIGS. 35A and FIG. 35B illustrate RT-PCR results verify the specificityof siPRKDC and siSRC.

FIG. 36 illustrates combined knockdown of GBC0905 target kinases PRKDCand SRC appears to inhibit DUX4 expression synergistically without celltoxicity or myogenic inhibition effects in FSHD-affected myotubes.

FIG. 37A and FIG. 37B illustrate GBC0905 treatment does not affect themRNA levels of PRKDC and SRC in patient biopsy-derived primary myotubes.

FIG. 38A and FIG. 38B illustrate GBC0905 inhibits PRKDC and SRCactivities in patient biopsy-derived primary myocytes.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure describes the use of Src, Tie, Abl, Flt, Trk,Yes, FAK, PRKDC kinase family inhibitors to treat subjects with muscularanomalies such as facioscapulohumeral muscular dystrophy (FSHD). Thekinase inhibitors may be administered singly, in combination, or incombination with other compounds or therapies such as a cell therapy. Insome embodiments, the kinase inhibitor is rebastinib, or a salt ofanalog thereof, or one or more compounds according to any of formulasI-VI. This disclosure also provides cell-based assays to identifycandidate compounds flat reduce or eliminate DUX4 expression.

Examples of Src, Tie, Abl, Trk, Fit, Yes, FAK, PRKDC kinase familyinhibitors that arc used in the present methods and compositions includeprimarily rebastinib and analogues or salts of thereof, sorafenib andanalogues or salts thereof, doramapimod and analogues or salts thereof,imatinib and analogs of thereof, PP2 and analogues or salts thereof, acompound of FIGS. 1-5 (or analogues or salts thereof), or a compound ofany one of Formulas (I)-(VII) (or analogues or salts thereof). In someembodiments, the Src, Tie, Abl, Trk, Flt, Yes, FAK, PRKDC kinase familyinhibitors modulate DUX4 activity. In other embodiments, the Src, Tie,Abl, Trk, Flt, Yes, FAK, PRKDC kinase family inhibitors downregulateDUX4 activity

TABLE 1 Representative Src, Tie, Abl, Trk, Flt, Yes, FAK kinase familiesinhibitors that downregulate the expression of DUX4. Quantitation % ofDUX4 DUX4 reduction @the EC50 Compound Target Effect, Y/N lowestsignificant [C] (nM) A419259 Src N Asciminib Src N AZM475271 Src N/ABosutinib Src Y 70.58% (3 μM)   N/A Crenolanib Src N/A Dasatinib Src N/ADCC2036 Src Y 66.39% (0.3 μM)  117.5 Y 51.75% (0.05 μM) 37.87 Y 79.76%(0.88 μM) 178.5 Y 82.94% (0.88 μM) 75.97 Erlotinib Src N/A KB SRC4 Src NLCB Src N 03-0110 PP1 Src N/A PP2 Src Y 41.77% (0.03 μM) 153.3 Y 66.61%(0.88 μM) 287.2 Saracatinib Src N/A Src I1 Src N XL228 Src Y ForetinibTie2 N/A Pexmetinib Tie2 N/A LDC1267 Axl N/A PD173074 PDGFR N/A NVP-EphB4 N/A BHG712 Ponatinib Abl N/A Flumatinib Abl Y 76.09% (2.08 μM)82.05 Imatinib Abl Y 61.13% (2.08 μM) 380.3 Asciminib Abl N AT9283 AblN/A AZD3463 Abl N/A Bafetinib Abl Y 67.90% (2.08 μM) 132.3 GNF-5 Abl NG2D824 Abl Y Lyn-IN-1 Abl Y 70.73% (0.88 μM) 174.6 Nilotinib Abl Y76.71% (5 μM)   N/A

The compounds, methods and compositions disclosed herein may be used totreat subjects with muscular degenerative diseases or muscular disordersstemming from a variety of causes, including, but not limited, to,genetic disorders, sporadic diseases, cachexia, muscle strain, muscleinjury, muscle atrophy, as well as sarcopenia and the general agingprocess. The disclosed compounds may be administered to a subject by avariety of routes, including but not limited to, orally, intravenously,intramuscularly, subcutaneously, and transdermally. Without wishing tobe bound by theory, the compounds may block de-repression or activationof DUX4 and/or interfere with the activity of DUX4 subsequent tode-repression As a result of administration of compounds provided herein(e.g., a compound of FIGS. 1-5, or a compound of any one of Formulas(I)-(VII), subjects may experience improvements in muscle strength,performance, stamina and reduced symptoms cf muscle weakness.

In some embodiments, compounds as described herein administeredparenterally may be formulated in an aqueous solution. For parenteraladministration of compounds described herein (e.g., rebastinib or saltsor analogues thereof or one or more compounds according to any offormulas I-VI) in an aqueous solution, the solution may be buffered andthe liquid formulation first rendered isotonic with sufficient saline orglucose. Such aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and/or intraperitoneal administration. Forexample, one dosage may be dissolved in 1 ml of isotonic NaCl solutionand either added to 1000 ml of hypodermoclysis fluid or injected at theproposed site of infusion, (see for example, “Remington's PharmaceuticalSciences” 15th Edition, pages 1035-1038 and 1570-1580).

In some embodiments, compounds as described herein administeredparenterally may be formulated in an oil-based solution. For parenteraladministration of compounds described herein (e.g. rebastinib oranalogues or salts thereof or compounds according to any of formulasI-VI) in an oil-based solution, the solution may comprise one or more ofan excipient such as PhytoSolve, Myglyol 810 N (e.g. 45% in solution).Phosal (e g. 50% in solution), medium-chain triglyceride (MCT) oil (e.g.20% MCT in aqueous solution), soybean phospholipids (e.g., 5% in aqueoussolution), or Polysorbate 80 (Tween-20, e g. 5% in solution). Thepresent disclosure describes the use of Src, Abl, Tic2, Flt, Yes, FAK,Trk, or PRKDC kinases inhibitors (e.g., a compound of FIGS. 1-5,rebastinib (or salt or analog thereof) or one or more compounds of anyone of Formulas (I)-(VII) (or any combination thereof, e g, Srcinhibitor and a PRKDC inhibitor) to treat subjects with musculardeficiencies such as FSHD The Src, Abl, Tic2, Flt, Yes, FAK, PRKDCand/or Trk inhibitors may be administered alone or in combination withother compounds or therapies such as a cell therapy. The Abl inhibitorsmay be administered alone or in combination with ether compounds ortherapies such as a cell therapy The Tie2 inhibitors may be administeredalone or in combination with other compounds or therapies such as a celltherapy. The Flt inhibitors may be administered alone or in combinationwith other compounds or therapies such as a cell therapy. The Yesinhibitors may be administered alone or in combination with ethercompounds or therapies such as a cell therapy. The FAK inhibitors may beadministered alone or in combination with other compounds or therapiessuch as a cell therapy. The TRK inhibitors may be administered alone orin combination with other compounds or therapies such as a cell therapy.

Examples of Src, Tie2, Abl, FAK, Flt, Yes, Trk, and/or PRKDC inhibitorsthat are used in the present methods and compositions include but arenot limited to one or more of the compounds described in any one ofFIGS. 1-5. In some embodiments, the compound used to treat subjects withmuscular deficiencies such is FSHD is rebastinib or analogs or saltsthereof. In some cases, the compound used to treat subjects withmuscular deficiencies such as FSHD is one or more compounds according toany of formulas I-VI. In some embodiments, the compound used to treatsubjects with muscular deficiencies such as FSHD is rebastinib oranalogs or salts thereof. In some embodiments, the compound used totreat subjects with muscular deficiencies such as FSHD is PP1 or analogsor salts thereof. In some embodiments, the compound used to treatsubjects with muscular deficiencies such as FSHD is PP2 or analogs orsalts thereof. In some embodiments, the compound used to treat subjectswith muscular deficiencies such as FSHD is sorafenib or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is doramapimod or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is imatinib or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is rebastinib or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is pamapimod or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is bosutinib, or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is ponatinib, or analogs or saltsthereof. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is a SRC inhibitor. In someembodiments, the compound used to treat subjects with musculardeficiencies such as FSHD is a PRKDC inhibitor In some embodiments, thecompound used to treat subjects with muscular deficiencies such is FSHDis a single compound that functions as both a PRKDC inhibitor and a SRCinhibitor. In some embodiments, the compound used to treat subjects withmuscular deficiencies such as FSHD is a mixture of compounds thatincludes a PRKDC inhibitor and a SRC inhibitor. In some embodiments, thecompound used to treat subjects with muscular deficiencies such as FSHDis a mixture of compounds that includes a PRKDC inhibitor and a SRCkinase family inhibitor.

Subjects to be Treated

The subjects treated by the methods and compositions provided herein mayhave or may be suspected of having any of a number cf musculardegenerative diseases and muscular disorders. In some cases, the subjecttreated by the methods and compositions provided herein has, or issuspected of having, dysregulated DUX4 expression or activity (e.g.,upregulated DUX4 expression or activity). In some cases, the subjecttreated by the methods and compositions provided herein has, or issuspected of having, dysregulated DUX4 expression or activity (e.g.,upregulated DUX4 expression) at compared to a control, such as the level(or absence) of DUX4 expression in healthy tissue In some cases, theDUX4 expression is assayed in comparison to a different gene, such as ahousekeeping gene In some cases, the subject treated by the methods andcompositions provided herein has detectable DUX4 expression or activity,or DUX4 expression or activity that is above a negligible amount. Themethods and compositions herein may include methods or compositions fortreating a subject suffering or suspected to be suffering from FSHD orother muscular or neuromuscular dystrophy. In some cases, the musculardystrophy is facioscapulohumeral muscular dystrophy-1 (FSHD1). In somecases, the muscular dystrophy is facioscapulohumeral musculardystrophy-2 (FSHD2). In some cases the muscular or neuromusculardystrophy is one of the following disorders: Becker muscular dystrophy,Duchenne muscular dystrophy, myotonic dystrophies types 1 and 2,nemaline myopathy or spinal muscular atrophy.

In some cases, a subject treated by the methods or compositions providedherein may be treated for a disease or disorder associated withupregulated DUX4 expression or activity. In some cases, the disease ordisorder associated with upregulated DUX4 expression or activity is achronic disease or disorder. In some cases, the disease or disorderassociated with upregulated DUX4 expression or activity is a non-acutedisease or disorder. In some cases, the disease or disorder associatedwith upregulated DUX4 expression or activity is a muscular disease ordisorder, or deficiency. In some cases, the disease or disorderassociated with upregulated DUX4 expression or activity is not cancer.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (1):

-   -   wherein E1 is phenyl, and wherein the E1 ring is substituted        with one to three R16 moieties;    -   wherein A is selected from the group consisting of imidazolyl,        and pyrazolyl;    -   G1 is a heteroaryl taken from the group consisting of pyrrolyl,        furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,        tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and        pyrimidinyl, G4 is a heterocyclyl taken from the group        consisting of oxetanyl, azetadinyl, tetrahydrofuranyl,        pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl,        thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,        morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,        thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl,        diazepinyl, tropanyl, and homotropanyl;    -   A ring is substituted at any substitutable position with one A1        moiety, wherein A1 is selected from the group consisting of:

-   -   and wherein the symbol (**) is the point of attachment to the A        ring of formula I;    -   and wherein — indicates either a saturated or unsaturated bond;    -   the A ring is optionally substituted with one or more R2        moieties;    -   X2 is a direct bond wherein E1 is directly linked to the NR3        group of formula I;    -   X3 is —O—;    -   V, V1, and V2 are each independently O or represent two        hydrogens attached to the methylene carbon to which the V, V1,        or V2 is attached;    -   each Z3 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C8carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl        moiety can be partially or fully fluorinated, cyano, hydroxyl,        methoxy, oxo, (R3)₂NC(O)—, (R4)₂NC(O)—, —N(R4)C(O)R8,        (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R₅, —N(R4)SO₂R8, —(CH₂)N(R3)₂,        —(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)N(R4)₂,        —O(CH₂)_(q)O—C1-C6alkyl,—N(R3)(CH₂)_(q)O—C1-C6alkyl,        —N(R3)(CH₂)_(q)N(R4)₂, —O(CH2)_(q)R5, —N(R3)(CH₂)_(q)R5,        —C(O)R5, —C(O)R8, and nitro;    -   in the event that Z3 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl,        C1-C6alkoxyC₂-C₆alkyl, (R4)₂N—C₂-C₆alkyl,        (R4)₂N—C₂-C6alkylN(R4)-C₂-C₆alkyl,        (R4)₂N—C₂-C₆alkyl-O—C₂-C₆alkyl, (R4)₂NC(O)—C1-C6alkyl,        carboxyC1-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-,        —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO₂R8, —C(O)R8,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(q)O(CH₂)_(n)G1,        —(CH₂)_(q)O(CH₂)_(n)G4, —(CH₂)_(q)N(R3)(CH₂)_(n)G1,        —(CH₂)_(q)N(R3)(CH₂)_(n)G4, —(CH₂)_(q)NHC(O)(CH₂)_(n)R5,        —(CH₂)_(q)C(O)NH(CH₂)_(n)R₅, —(CH₂)_(q)C(O)R5,        —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5, —(CH₂)_(q)NR4(CH₂)_(q)R5, and        —(CH₂)_(q)O(CH₂)_(q)R5;    -   in the event that Z4 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z6 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        hydroxyl, hydroxyC1-C6alkyl, hydroxyC₂-C₆ branched alkyl,        C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC₂-C₆ branched        alkyl-, C2-C6 branched alkoxy-, C1-C6alkylthio-, (R3)₂N—,        —N(R3)C(O)R8, (R4)₂N—, —R5, —N(R4)C(O)R8, —N(R3)SO₂R6,        —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5, —SO₂NH(R4), halogen,        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully        or partially fluorinated, —O(CH₂)_(q)N(R4)₂,        —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)O—C1-C6alkyl,        —N(R₃)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, N(R3)(CH₂)_(q)R₅,        —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17, —(CH₂)_(n)R17, —R17,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,        —(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and        —(CH₂)_(n)N(R3)(CH2)_(n)G4;    -   each R2 is selected from the group consisting of Z3-substituted        aryl, Z3-substituted G1-, Z3-substituted G4-, C1-C6alkyl,        branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein        the alkyl group is fully or partially fluorinated;    -   wherein each R3 is independently and individually selected from        the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-cartocyclyl, and Z3-substituted phenyl;    -   each R4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-,        dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched        C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branched        C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂,        —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, C3-C7-carbocyclyl, hydroxyl        substituted C3-C7-carbocyclyl-, alkoxy substituted        C3-C7-carbocyclyl-, dihydroxyl substituted C3-C7-carbocyclyl-,        and —(CH₂)_(n)R17;    -   each R5 is independently and individually selected from the        group consisting of

-   -   and wherein the symbol (##) is the point of attachment of the R5        moiety;    -   each R6 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, G1, and G4;    -   each R7 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl-,        dihydroxyC₂-C₆alkyl-, C₂-C₆alkoxyC₂-C₆alkyl-, branched        C3-C7alkyl-, branched hydroxyC₂-C₆ alkyl-, branched        C₂-C₆alkoxyC₂-C₆alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(q)R5, —)CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,        C3-C7-carbocyclyl, hydroxyl substituted C3-C7-carbocyclyl-,        alkoxy substituted C3-C7-carbocyclyl-, dihydroxy substituted        C3-C7-carbocyclyl, and —(CH₂)_(n)R17;    -   each R8 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        fluoroC1-C6alkyl wherein the alkyl moiety is partially or fully        fluorinated, C3-C7-carbocyclyl, phenyl-, phenylC1-C6alkyl-, G1,        G1-C1-C6alkyl-, G4, G4-C1-C6alkyl-, OH, C1-C6alkoxy, N(R3)₂,        N(R4)₂, and R5;    -   each R9 is independently and individually selected from the        group consisting of H, F, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, phenyl-C1-C6alkyl-, —(CH₂)_(n)G1, and        —(CH₂)_(n)G4;    -   each R10 is independently and individually selected from the        group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂, OH,        C1-C6alkoxy, and —N(R4)₂;    -   each R14 is independently and respectively selected from the        group consisting of H, C1-C6alkyl, branched C3-C6alkyl, and        C3-C7-carbocyclyl;    -   R16 is independently and individually selected from the group        consisting of fluorine and methyl;    -   each R17 is taken from the group comprising phenyl, naphthyl,        pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,        isothiazolyl, imdazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,        oxetanyl, azctadinyl, tetrahydrofuranyl, oxazolinyl,        oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,        dioxalinyl, azepinyl, oxepinyl, and diazepinyl;    -   wherein R17 can be optionally substituted with an R3        substituent,    -   R19 is H or C1-C6 alkyl;    -   n is 0-6, p is 1-4, q is 2-6; r is 0 or 1; t is 1-3, and v is 1        or 2.

Another embodiment provides a method for treating a musculardegenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (I), and further described by the structure ofFormula (II):

-   -   wherein A is pyrazolyl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, selected fromthe group consisting of:

-   -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(pyridin-3-yloxy)phenyl)urea;    -   1-(3)-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea;    -   1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;        1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(methylcarbamoyl)pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol        -5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(isopropylamino)pyridin-4-yloxy)-3-methylphenyl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,        and    -   1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,or a pharmaceutically acceptable salt thereof.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 1.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 2.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 3.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 4.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 5.

Another embodiment proves the method of treating a muscular degenerativedisorder wherein the muscular degenerative disorder is selected fromfacioscapulohumeral muscular dystrophy (FSHD), facioscapulohumeralmuscular dystrophy-1 (FSHD1), facioscapulohumeral muscular dystrophy-2(FSHD2), Becker muscular dystrophy, Duchenne muscular dystrophy,myotonic dystrophies type 1, myotonic dystrophies types 2, nemalinemyopathy or spinal muscular atrophy. Another embodiment proves themethod wherein the subject is a human.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (III):

-   -   wherein    -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹,—S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   n is 0-5;    -   L¹ is absent or *—(CR^(a)R^(b))—C(═O)—, wherein * denotes        attachment point to the carbonyl carbon;    -   R^(a) and R^(b) are independently selected from hydrogen,        C₁-C₆alkyl, or C₁-C₆ haloalkyl;    -   or R^(a) and R^(b) are taken together with the carbon to which        they are attached to form a 3-, 4-, 5-, or 6-membered cycloalkyl        or a 3-, 4-, 5-, or 6-membered heterocycloalkyl;    -   each R² is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   or two R² on adjacent atoms are taken together with the atoms to        which they are attached to form an unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   m is 0-4;    -   L² is absent, —O—, —O—(C₁-C₄ alkylene)-, or —NR^(c)—C(═O)—;    -   each R^(c) is independently selected from hydrogen, C₁-C₆ alkyl,        or C₁-C₆ haloalkyl;    -   R³ is unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein when R³ is        substituted, it is substituted by 1-3 R⁴;    -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R²⁰, or R²¹ is substituted,        substituents on the R¹, R², R⁴, R²⁰, or R²¹ are independently        selected at each occurrence from halogen, —CN, —NO₂, —OR²²,        —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²NR²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;    -   each R²² is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²² groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³ is independently selected from C₁-C₆alkyl, C₃-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (IV):

wherein

-   -   L is absent or —C₁-C₄ alkylene;    -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   or two R¹ on adjacent atoms are taken together with the atoms to        which they are attached to form a unsubstituted or substituted        carbocycle, or unsubstituted or substituted heterocycle; wherein        if the carbocycle or heterocycle is substituted, it is        substituted with 1-3 R⁷;    -   each R⁷ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   n is 0-5;    -   R² and R⁴ are each independently hydrogen, or —NR⁵R⁶, or        unsubstituted or substituted heterocycle;    -   each R⁵ and R⁶ is independently hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   or R⁵ and R⁶ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle;    -   R³ is hydrogen, halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R² and R³ are taken together with the atoms to which they are        attached to form a unsubstituted or substituted carbocycle, or        unsubstituted or substituted heterocycle; wherein if the        carbocycle or heterocycle is substituted, it is substituted with        1-3 R⁸;    -   each R⁸ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   or two R⁷ on the same carbon atom are taken together to form a        C═O, or C═S;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or R²¹is        substituted, substituents on the R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or        R²¹are independently selected at each occurrence from halogen,        —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²²,        —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³,        —SO₂NR²²R²², —NR²²SO₂R²³, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        monocyclic cycloalkyl, monocyclic heterocycloalkyl, phenyl,        benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;    -   each R²² is independently selected from hydrogen, C₁-C₆alkyl,        C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered        heteroaryl, and 6-membered heteroaryl;    -   or two R²² groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³ is independently selected from C₁-C₆alkyl, C₁-C₆        hydroxyalkyl, C₁-C₆alkyl C₃-C₆ cycloalkyl, phenyl, benzyl,        5-membered heteroaryl, and 6-membered heteroaryl;

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (V):

-   -   wherein    -   X¹ is N or CR¹;    -   R¹ is hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   X² is N or CR²;    -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,        —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰, —S(═O)₂NR²¹R²¹,        —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹,        —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   X³ is N or CR³;    -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,        —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰, —S(═O)₂NR²¹R²¹,        —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹,        —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   X⁴ is N or CR⁴;    -   R⁴ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,        —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰, —S(═O)₂NR²¹R²¹,        —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹,        —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl;    -   wherein 0, 1, or 2 of X¹, X², X³, and X⁴ are N;    -   R⁵ is hydrogen, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl; wherein if R⁵ is        substituted, it is substituted with 1-3 R⁹;    -   each R⁹ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO², —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR₂₁C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl;    -   R⁶ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R⁵ and R⁶ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹³;    -   each R¹³ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        ——NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   R⁷ is hydrogen, unsubstituted or substituted cycloalkyl,        unsubstituted or substituted heterocycloalkyl, unsubstituted or        substituted aryl, unsubstituted or substituted heteroaryl,        unsubstituted or substituted —C₁-C₆-alkylene-cycloalkyl, or        —C(═O)R¹¹;    -   R¹¹ unsubstituted phenyl, or phenyl substituted by 1-3 R¹²,    -   each R¹² is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalky,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl, unsubstituted or substituted        —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-heterocycloalklyl, unsubstituted or substituted        —C₁-C₆-alkylene-aryl, or unsubstituted or substituted        —C₁-C₆-alkylene-heteroaryl;    -   R⁸ is hydrogen, C₁-C₆alkyl or C₁-C₆ haloalkyl;    -   or R⁷ and R⁸ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹⁰;    -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   each R₂₀ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R², R³, R⁴, R⁷, R⁹, R¹⁰, R¹², R¹³, R²⁰, or        R²¹is substituted, substituents on the R², R³, R⁴, R⁷, R⁹, R¹⁰,        R¹², R¹³, R²⁰, or R²¹are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —C(═O)NR²²R²², —C(═O)NR²²—OR²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, monocyclic heterocycloalkyl substituted with a        R²³, phenyl, benzyl, 5-membered heteroaryl, and 6-membered        heteroaryl; or two substituents on the same carbon atom are        taken together to form a C═O or C═S;    -   each R²²is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²²groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³is independently selected from C₁-C₆ alkyl, C₃-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (VI):

wherein:

-   -   X¹ and X² are independently N or CH;    -   X³ is N or CR³;    -   R³ is hydrogen, —CN, or -L-Ar,    -   X⁴ is N or CR⁴;    -   R⁴ is hydrogen, or -L-Ar;    -   wherein one of X³ and X⁴ is C-L-Ar;    -   L is —NH—, —O—, —S—, —C₁-C₂ alkylene-, or        -heterocycloalkylene-C(═O)—;    -   Ar is substituted or unsubstituted phenyl or substituted or        unsubstituted 5- or 6-membered heteroaryl; wherein when Ar is        substituted, it is substituted with 1-3 R⁶;    -   each R⁶ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)²NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —(C₁-C₄ alkylene)-C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,        —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R⁶ on adjacent atoms are taken together with the atoms to        which they are attached to form an unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   each R⁵ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁵, R⁶, R²⁰, or R²¹ is substituted,        substituents on the R⁵, R⁶, R²⁰, or R²¹ are independently        selected at each occurrence from halogen, —CN, —NO₂, —OR²²,        —CO₂R²², —C(═O)R²³, —OC(═O)R²³, —C(═O)NR²²R²², —NR²²R²²,        —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³,        —SO₂NR²²R²², C₁-C₆ alkyl, C₁-C₆ haloalkyl, monocyclic        cycloalkyl, monocyclic heterocycloalkyl, phenyl, benzyl,        5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;    -   each R²²is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²²groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³is independently selected from C₁-C₆alkyl, C₃-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method for treating amuscular degenerative disorder in a subject in need thereof comprisingadministering to the subject in need thereof a composition comprising acompound, or a pharmaceutically acceptable salt thereof, having thestructure of Formula (VII):

wherein:

-   -   X¹ is —S—, —O—, or —NR¹—;    -   R¹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl; wherein when R¹ is substituted, it is        substituted by 1-3 R⁷;    -   each R⁷ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, ——C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   X² is N or CR²;    -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,        —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰, —S(═O)₂NR²¹R²¹,        —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹,        —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl; wherein when R² is substituted, it is        substituted by 1-3 R⁸;    -   each R⁸ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   X³ is N or CR³; wherein X² and X³ are not both N;    -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,        —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰, —S(═O)₂NR²¹R²¹,        —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹,        —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl, unsubstituted or substituted        —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-aryl, or unsubstituted or substituted        —C₁-C₆-alkylene-heteroaryl; wherein when R³ is substituted, it        is substituted by 1-3 R⁹;    -   each R⁹ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)₂R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   Ar is a 6-membered aromatic ring comprising 0-2 nitrogen atoms;    -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR⁵, —SH,        —SR⁵, —NO₂, —NR⁶R⁶, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)R⁵,        —S(═O)₂NR⁶R⁶, —C(═O)R⁵, —OC(═O)R⁵, —C(═O)OR⁶, —OC(═O)OR⁶,        —C(═O)NR⁶R⁶, —OC(═O)NR⁶R⁶, —NR⁶C(═O)NR⁶R⁶, —NR⁶C(═O)R⁵,        —NR⁶C(═O)OR⁶, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl, unsubstituted or substituted        —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-aryl, or unsubstituted or substituted        —C₁-C₆-alkylene-heteroaryl;    -   each R⁵ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein if R⁵ is        substituted, it is substituted by 1-3 R¹⁰;    -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   each R⁶is independently selected from hydrogen, unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein if R⁶ is        substituted, it is substituted by 1-3 R¹¹;    -   each R¹¹ is independently halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰,        —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,        —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹,        —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰,        —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰, or R²¹is        substituted, substituents on the R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰,        or R²¹ are independently selected at each occurrence from        halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²²,        —NR²²R²², —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³,        —SO₂R²³, —SO₂NR²²R²², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, benzyl substituted with        phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;    -   each R²²is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²² groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³is independently selected from C₁-C₆ alkyl, C₁-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 18 or19.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 20 or21.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 22 or23.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 24 or25.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a compound selected from the compounds provided in FIG. 26 or27.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound selected from the compounds provided in FIG. 28 or 29. In someembodiments, this disclosure provides a method of treating a musculardegenerative disorder wherein the muscular degenerative disorder isselected from facioscapulohumeral muscular dystrophy (FSHD),facioscapulohumeral muscular dystrophy-1 (FSHD1), facioscapulohumeralmuscular dystrophy-2 (FSHD2), Becker muscular dystrophy, Duchennemuscular dystrophy, myotonic dystrophies type 1, myotonic dystrophiestypes 2, nemaline myopathy, spinal muscular atrophy, congenital myotonicdystrophy, congenital muscular dystrophies, LAMA2, SEPN1, GNEmyopathies, and SMARD1. In some embodiments, this disclosure provides amethod of treating a muscular degenerative disorder in a subject in needthereof, wherein the subject is a human.

The subjects are preferably human subjects or patients, but in somecases may be non-human subjects, (e.g., non-human mammals). Examples ofnon-human mammals include, but are not limited to, non-human primates(e.g., apes, monkeys, gorillas), rodents (e.g., mice, rats), cows, pigs,sheep, horses, dogs, cats, and rabbits.

Subjects who may benefit from the methods and compositions providedherein may be suffering or suspected to be suffering from FSHD or othermuscular or neuromuscular dystrophy at any stage of disease. Forexample, such subjects may be suffering from FSHD at an early stage ofpathogenesis and may even be unaware of disease symptoms. In some cases,a subject may have other symptoms that may appear early in thepathogenesis of FSHD, such as weakness around the eyes and/or the mouth,an inability to purse or pucker the lips, a difficulty with turning upthe comers of the mouth when smiling, and an inability to close theeyes. Subjects who may benefit from treatment according to the methodsand compositions provided herein may be suffering from FSHD at anintermediate stage of pathogenesis. Such subjects may experience musclepain and aching, including, but not limited to aching in the area aroundthe shoulders; a loss of stability around the shoulders, including, butnot limited to a loss of stability that impedes the subject's ability tothrow objects or lift the arms above the head; and/or unequal muscleweakening, including, but not limited to the biceps, triceps, deltoids,and lower arm muscles. In some cases, subjects who may benefit fromtreatment according to the methods and compositions provided herein maybe suffering from FSHD at a late stage of pathogenesis Such subjects mayexperience weakening of abdominal muscles and hip muscles, which maylead to an exaggerated curvature of the lower spine, and/or weakening ofmuscles throughout the body, including, but not limited to muscles ofthe foot, ankle, hips, and abdomen.

Subjects in need of treatment according to the methods and compositionsprovided herein may be male or female. Subjects may include adults,teenagers, adolescents, children, toddlers, infants, and neonates. Suchsubjects may be of a range of ages, which may include >10 minutesold, >1 hour old, >1 day old, >1 month old, >2 months old, >6 monthsold, >1 year old, >2 years old, >5 years old, >10 years old, >15 yearsold, >18 years old, >25 years old, >35 years old, >45 years old, >55years old, >65 years old, >80 years old, <80 years old, <70 years old,<60 years old, <50 years old, <40 years old, <30 years old, <20 yearsold or <10 years old. The subject may be a neonatal infant. In somecases, the subject is a child or an adult. In some examples, the tissueis from a human of age 2, 5, 10 or 20 hours. In other examples, thetissue is from a human of age 1 month, 2 months, 3 months, 4 months, 5months, 6 months, 9 months or 12 months. In some cases, the tissue isfrom a human of age 1 year, 2 years, 3 years, 4 years, 5 years, 18years, 20 years, 21 years, 23 years, 24 years, 25 years, 28 years, 29years, 31 years, 33 years, 34 years, 35 years, 37 years, 38 years, 40years, 41 years, 42 years, 43 years, 44 years, 47 years, 51 years, 55years, 61 years, 62 years, 65 years, 70 years, 77 years, or 85 years.Subjects may have differing genetic backgrounds, including differentracial groups or genetically admixed populations.

Effects or Activity of Compounds Provided Herein

In some embodiments, treatment of a subject in need thereof (e g. anFSHD patient) with compounds described herein (e.g. rebastinib, or ananalog or salt thereof, or a compound according to any one of formulasI-VII) results in a decrease in DUX4 activity in a cell or tissue of thesubject of at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80%, at least 90%, atleast 95%, at least 98%, or 100% compared to an untreated cell or tissuefrom the subject. In some embodiments, treatment of a subject in needthereof (e.g. an FSHD patient) with compounds described herein (e g.rebastinib, or an analog or salt thereof, or a compound according to anyone of formulas I-VII) results in a decrease in DUX4 effector activity(e.g., expression or function) in a cell or tissue of the subject of atleast 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 95%, at least 98%, or100% compared to an untreated cell or tissue from the subject. The cellin which DUX4 activity is assessed is preferably a muscle cell. Thetissue in which DUX4 activity is assessed is preferably muscle tissue.Exemplary DUX4 effectors (e g. target genes) include CCNA1, KHDC1L.LEUTX, M8D3L2, PRAMEF2, PRAMEF6, SPRYD5, TRIM43, TRIM49, ZNF296, andZSCAN4. As such, in some embodiments, expression or activity of thesetarget genes may be assessed in order to measure or detect DUX4expression or activity. For example, western blot or other assay may beused to detected expression of target gene protein In some cases,quantitative PCR, RNAseq, gene array, and/or Northern blot or otherassay may be used to detect expression of target gene RNA.

In some cases, following administration of a compound provided herein toa subject, the resulting DUX4 activity or function of the subject mayclosely resemble that of a normal, healthy cell or tissue that isunaffected with a muscle deficiency disorder such as FSHD. In somecases, the resulting DUX4 activity or function may be the same as thatof a normal healthy cell or tissue (e g. non-FSHD affected cell ortissue), may be within about 2% of DUX4 activity or function in that ofa normal healthy cell or tissue (e.g., non-FSHD affected cell ortissue), may be within about 5% of DUX4 activity or Junction in that ofa normal healthy cell or tissue (e.g., non-FSHD affected cell ortissue), or may be within about 10% of DUX4 activity or function in thatof a normal healthy cell or tissue (e.g.. non-FSHD affected cell ortissue).

The compounds or agents provided herein may cause cells or tissue withirregular DUX4 expression (e g., an FSHD-affected skeletal muscle cellor tissue) to express DUX4 (mRNA and/or protein) at levels similar tothat of normal, healthy muscle cells (e g , non-FSHD affected cell ortissue), in some cases, the level of DUX4 expression may be reduced byat least 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 98%, or 100% following administration of a compoundprovided herein. In some cases, following administration of a compoundprovided herein to a subject, the resulting DUX4 expression of thesubject may closely resemble that of a normal, healthy cell or tissuethat is unaffected with a muscle deficiency disorder such as FSHD. Insome cases, the resulting DUX4 expression may be the same as that of anormal healthy cell or tissue (e.g., non-FSHD affected cell or tissue),may be within about 2% of the level of DUX4 expression in that of anormal healthy cell or tissue (e.g., non-FSHD affected cell or tissue),may be within about 5% of the level of DUX4 expression in that of anormal healthy cell or tissue (e.g., non-FSHD affected cell or tissue),or may be within about 10% of the level of DUX4 expression in that of anormal healthy cell or tissue (e.g., non-FSHD affected cell or tissue)DUX4 expression may be measured or detected using any known technique inthe art. For example, western blot or other assay may be used todetected expression of DUX4 protein, quantitative PCR, RNAseq, genearray, and/or Northern blot or other assay may be used to detectexpression of DUX4 RNA. In some cases, specific cell types may beanalyzed, such as muscle cells, myoblast cells, multi-nucleated cellsand/or myotubes

In some cases, a subject or patient with elevated DUX4 expression oractivity may have increased cell death or apoptosis in muscle cells ortissues (or other tissues) associated with the DUX4 expression oractivity As such, administration of a compound provided herein (e.g.,rebastinib or a salt of analog thereof, or one or more compoundsaccording to any of formulas I-VI) may treat such patient or subject bycausing a reduction or eradication of cell death or apoptosis that wascaused by the elevated DUX4 expression or activity. Such reduction incell death or apoptosis may be assessed by any assay known in the art,including a Caspase 3/7 cleavage or activity assay.

According to the methods provided herein, the compounds or agents, forexample rebastinib may have a half maximal effective concentration(EC₅₀) of less than 5 μM. In some examples, the compound or compoundsmay have an EC₅₀ less than about 5 μM, less than about 4 μM, less thanabout 3 μM, less than about 2 μM, less than about 1 μM, less than about500 nM, or less than about 100 nM. In a preferred embodiment, thecompound or compounds have an EC₅₀ of less than about 5 μM.

The compounds or agents provided herein may not be toxic toFSHD-affected skeletal muscle cells There may not be any increase incell death in FSHD-affected skeletal muscle cells contacted with acompound or agent provided herein compared to FSHD-affected skeletalmuscle cells not contacted by a compound or agent provided herein.

In some cases, the compounds or agents provided herein are administeredto a subject in order to reduce or eliminate the symptoms of FSHD. Suchsymptoms include, but are not limited to abdominal muscle weakness, poorcardiac or respiratory function, facial weakness, hip weakness, lowerleg weakness, depression, decreased energy, and skeletal muscle weaknessIn some cases, the compounds or agents provided herein are administeredto a subject to treat FSHD or ataxia.

In some cases, the compounds or agents provided herein are administeredto a subject in order to improve one or more functional measuresnegatively affected by FSHD. Such measures negatively affected includegrip strength (e.g. measured by a grip meter test), skeletal musclestrength, the sit-to-stand test, the stance-to-sit test, the step-uptest, the step-down test, antigravity tests, 6-minute walk test, andneuromuscular quality of life score (e.g. as measured by INQoL scores asin Sadjadi et al. Health Qualm Life Outcomes 2011; 9:114.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity in a subject in need thereof comprising administering tothe subject in need thereof a composition comprising a compound, or apharmaceutically acceptable salt thereof, having the structure ofFormula (I):

-   -   wherein E1 is phenyl, and wherein the E1 mg is substituted with        one to three R16 moieties;    -   wherein A is selected from the group consisting of imidazolyl,        and pyrazolyl,    -   G1 is a heteroaryl taken from the group consisting of pyrrolyl,        furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl,        tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and        pyrimidinyl;    -   G4 is a heterocyclyl taken from the group consisting of        oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl,        oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl,        tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,        thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl        S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,        tropanyl, and homotropanyl;    -   A ring is substituted at any substitutable position with one A1        moiety, wherein A1 is selected from the group consisting of

-   -   and wherein the symbol (**) is the point of attachment to the A        ring of formula I;    -   and wherein — indicates either a saturated or unsaturated bond;    -   the A ring is optionally substituted with one or more R2        moieties;    -   X2 is a direct bond wherein E1 is directly linked to the NR3        group of formula I;    -   X3 is —O—;    -   V, V1, and V2 are each independently O or represent two        hydrogens attached to the methylene carbon to which the V, V1,        or V2 is attached;    -   each Z3 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C8carbocyclyl, halogen, fluoroC1-C6alkyl wherein the alkyl        moiety can be partially or fully fluorinated, cyano, hydroxyl,        methoxy, oxo, (R3)₂NC(O)—, (R4)₂NC(O)—, —N(R4)C(O)R8,        (R3)₂NSO₂—, (R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —(CH₂)N(R3)₂,        —(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —N(R3)(CH2)_(q)O—C1-C6alkyl, —N(R3)(CH₂)_(q)N(R4)₂,        —O(CH2)_(q)R5, —N(R3)(CH₂)_(q)R5, —C(O)R5, —C(O)R8, and nitro;    -   in the event that Z3 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl,        C1-C6alkoxyC₂-C₆alkyl, (R4)₂N—C₂-C₆alkyl,        (R4)₂N—C₂-C6alkylN(R4)-C₂-C₆alkyl,        (R4)₂N—C₂-C₆alkyl-O—C₂-C₆alkyl, (R4)₂NC(O)—C1-C6alkyl,        carboxyC1-C6alkyl-, C1-C6alkoxycarbonylC1-C6alkyl-,        —C₂-C₆alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO₂R8, —C(O)R8,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(q)O(CH₂)_(n)G1,        —(CH₂)_(q)O(CH₂)_(n)G4, —(CH₂)_(q)N(R3)(CH₂)_(n)G1,        —(CH₂)_(q)N(R3)(CH₂)_(n)G4, —(CH₂)_(q)NHC(O)(CH₂)_(n)R5,        —(CH₂)_(q)C(O)NH(CH₂)_(q)R₅, —(CH₂)_(q)C(O)R5,        —(CH₂)_(q)OC(O)R5, —(CH₂)_(q)R5, —(CH₂)_(q)NR4(CH₂)_(q)R5, and        —(CH₂)_(q)O(CH₂)_(q)R5;    -   in the event that Z4 contains an alkyl or alkylene moiety, such        moieties may be further substituted with one or more        C1-C6alkyls;    -   each Z6 is independently and individually selected from the        group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        hydroxyl, hydroxyC1-C6alkyl, hydroxyC₂-C₆ branched alkyl,        C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-, C1-C6alkoxyC₂-C₆ branched        alkyl-, C₂-C₆ branched alkoxy-, C1-C6alkylthio-, (R3)₂N—,        —N(R3)C(O)R8, (R4)₂N—, —R5, —N(R4)C(O)R8, —N(R3)SO₂R6,        —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5, —SO₂NH(R4), halogen,        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, fluoroC1-C6alkoxy wherein the alkyl is fully        or partially fluorinated, —O(CH₂)_(q)N(R4)₂,        —N(R3)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,        —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)O—C1-C6alkyl,        —N(R₃)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, N(R3)(CH₂)_(q)R₅,        —(NR3)_(r)R17, —(O)_(r)R17, —(S)_(r)R17, —(CH₂)_(n)R17, —R17,        —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1,        —(CH₂)_(n)O(CH₂)_(n)G4, —(CH₂)_(n)N(R3)(CH₂)_(n)G1, and        —(CH₂)_(n)N(R3)(CH2)_(n)G4;    -   each R2 is selected from the group consisting of Z3-substituted        aryl, Z3-substituted G1-, Z3-substituted G4-, C1-C6alkyl,        branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl        fluoroC1-C6alkyl wherein the alkyl is fully or partially        fluorinated, cyano, C1-C6alkoxy, and fluoroC1-C6alkoxy wherein        the alkyl group is fully or partially fluorinated;    -   wherein each R3 is independently and individually selected from        the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, and Z3-substituted phenyl;    -   each R4 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-,        dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched        C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branched        C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(p)N(R7)₂, —(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂,        —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3, C3-C7-carbocyclyl, hydroxyl        substituted C3-C7-carbocyclyl-, alkoxy substituted        C3-C7-carbocyclyl-, dihydroxyl substituted C3-C7-carbocyclyl-,        and —(CH₂)_(n)R17;    -   each R5 is independently and individually selected from the        group consisting of

-   -   and wherein the symbol (##) is the point of attachment of the R5        moiety;    -   each R6 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, G1, and G4;    -   each R7 is independently and individually selected from the        group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl-,        dihydroxyC₂-C₆alkyl-, C₂-C₆alkoxyC₂-C₆alkyl-, branched        C3-C7alkyl-, branched hydroxyC₂-C₆ alkyl-, branched        C₂-C₆alkoxyC₂-C₆alkyl-, branched dihydroxyC₂-C₆alkyl-,        —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,        C3-C7-carbocyclyl, hydroxyl substituted C3-C7-carbocyclyl-,        alkoxy substituted C3-C7-carbocyclyl-, dihydroxy substituted        C3-C7-carbocyclyl, and —(CH₂)_(n)R17;    -   each R8 is independently and individually selected from the        group consisting of C1-C6alkyl, branched C3-C7alkyl,        fluoroC1-C6alkyl wherein the alkyl moiety is partially or fully        fluorinated, C3-C7-carbocyclyl, phenyl-, phenylC1-C6alkyl-, G1,        G1-C1-C6alkyl-, G4, G4-C1-C6alkyl-, OH, C1-C6alkoxy, N(R3)₂,        N(R4)₂, and R5;    -   each R9 is independently and individually selected from the        group consisting of H, F, C1-C6alkyl, branched C3-C7alkyl,        C3-C7-carbocyclyl, phenyl, phenyl-C1-C6alkyl-, —(CH₂)_(n)G1, and        —(CH₂)_(n)G4;    -   each R10 is independently and individually selected from the        group consisting of CO₂H, CO₂C1-C6alkyl, —C(O)N(R4)₂, OH,        C1-C6alkoxy, and —N(R4)₂;    -   each R14 is independently and respectively selected from the        group consisting of H, C1-C6alkyl, branched C3-C6alkyl, and        C3-C7-carbocyclyl;    -   R16 is independently and individually selected from the group        consisting of fluorine and methyl;    -   each R17 is taken from the group comprising phenyl, naphthyl,        pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,        isothiazolyl, imdazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,        triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl,        oxetanyl, azctadinyl, tetrahydrofuranyl, oxazolinyl,        oxazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl,        dioxalinyl, azepinyl, oxepinyl, and diazepinyl;    -   wherein R17 can be optionally substituted with an R3        substituent,    -   R19 is H or C1-C6 alkyl;    -   n is 0-6, p is 1-4, q is 2-6; r is 0 or 1; t is 1-3, and v is 1        or 2.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (IX and further described bythe structure of Formula (II):

wherein A is pyrazolyl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from the group consisting of:

-   -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(pyridin-3-yloxy)phenyl)urea;    -   1-(3)-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylamino)pyridin-4-yloxy)phenyl)urea;    -   1-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-cyclopentyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(hydroxymethyl)pyridin-3-yloxy)phenyl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-methyl-3-(pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea;        1-(4-(2-carbamoylpyridin-4-yloxy)-2-fluorophenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(6-(methylcarbamoyl)pyridin-3-yloxy)phenyl)urea;    -   1-(4-(2-carbamoylpyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol        -5-yl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol        -5 -yl)urea;    -   1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-fluoro-4-(2-(isopropylamino)pyridin-4-yloxy)phenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea;    -   1-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-(isopropylamino)pyridin-4-yloxy)-3-methylphenyl)urea;    -   1-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea,        and    -   1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-ethyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising1-(3-tert-butyl-1-(quinolin-6yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea,or a pharmaceutically acceptable salt thereof.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 1.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 2.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 3.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 4.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in Figure 5. Anotherembodiment provides the method for modulating DUX4 activity wherein themodulation of DUX4 activity is inhibition of DUX4 activity.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (III):

wherein

-   -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   n is 0-5;    -   L¹ is absent or *—(CR^(a)R^(b))—C(═O)—, wherein * denotes        attachment point to the carbonyl carbon;        -   R^(a) and R^(b) are independently selected from hydrogen,            C₁-C₆alkyl, or C₁-C₆ haloalkyl;        -   or R^(a) and R^(b) are taken together with the carbon to            which they are attached to form a 3-, 4-, 5-, or 6-membered            cycloalkyl or a 3-, 4-, 5-, or 6-membered heterocycloalkyl;    -   each R² is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   or two R² on adjacent atoms are taken together with the atoms to        which they are attached to form an unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, or unsubstituted or        substituted heteroaryl;    -   m is 0-4;    -   L² is absent, —O—, —O—(C₁-C₄ alkylene)-, or —NR^(c)—C(═O)—;    -   each R^(c) is independently selected from hydrogen, C₁-C₆ alkyl,        or C₁-C₆ haloalkyl;    -   R³ is unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl; wherein when R³ is        substituted, it is substituted by 1-3 R⁴;        -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R²⁰, or R²¹ is substituted,        substituents on the R¹, R², R⁴, R²⁰, or R²¹ are independently        selected at each occurrence from halogen, —CN, —NO₂, —OR²²,        —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²NR²³, C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;    -   each R²² is independently selected from hydrogen, C₁-C₆ alkyl,        C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl;    -   or two R²² groups are taken together with the N atom to which        they are attached to form a N-containing heterocycle; and    -   each R²³ is independently selected from C₁-C₆alkyl, C₃-C₆        cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (IV):

wherein

-   -   L is absent or —C₁-C₄ alkylene;    -   Ar is phenyl or 5- or 6-membered heteroaryl;    -   each R¹ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   or two R¹ on adjacent atoms are taken together with the atoms to        which they are attached to form a unsubstituted or substituted        carbocycle, or unsubstituted or substituted heterocycle; wherein        if the carbocycle or heterocycle is substituted, it is        substituted with 1-3 R⁷;        -   each R⁷ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   n is 0-5;    -   R² and R⁴ are each independently hydrogen, or —NR⁵R⁶, or        unsubstituted or substituted heterocycle;        -   each R⁵ and R⁶ is independently hydrogen, unsubstituted or            substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆            alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,            unsubstituted or substituted cycloalkyl, unsubstituted or            substituted heterocycloalkyl, unsubstituted or substituted            aryl, unsubstituted or substituted heteroaryl, unsubstituted            or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or            substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted            or substituted —C₁-C₆-alkylene-aryl, or unsubstituted or            substituted —C₁-C₆-alkylene-heteroaryl;        -   or R⁵ and R⁶ are taken together with the N atom to which            they are attached to form an unsubstituted or substituted            N-containing heterocycle;    -   R³ is hydrogen, halogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R² and R³ are taken together with the atoms to which they are        attached to form a unsubstituted or substituted carbocycle, or        unsubstituted or substituted heterocycle; wherein if the        carbocycle or heterocycle is substituted, it is substituted with        1-3 R⁸;        -   each R⁸ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,            —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;        -   or two R⁷ on the same carbon atom are taken together to form            a C═O, or C═S;    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or R²¹is        substituted, substituents on the R¹, R², R⁴, R⁵, R⁶, R⁷, R²⁰, or        R²¹are independently selected at each occurrence from halogen,        —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²²,        —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³,        —SO₂NR²²R²², —NR²²SO₂R²³, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        monocyclic cycloalkyl, monocyclic heterocycloalkyl, phenyl,        benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆alkyl,            C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, phenyl, benzyl,            5-membered heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³ is independently selected from C₁-C₆alkyl, C₁-C₆            hydroxyalkyl, C₁-C₆alkyl C₃-C₆ cycloalkyl, phenyl, benzyl,            5-membered heteroaryl, and 6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 0activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (V):

-   -   wherein    -   X¹ is N or CR¹;        -   R¹ is hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl;    -   X² is N or CR²;        -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   X³ is N or CR³;        -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   X⁴ is N or CR⁴;        -   R⁴ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl;    -   wherein 0, 1, or 2 of X¹, X², X³, and X⁴ are N;    -   R⁵ is hydrogen, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;        -   wherein if R⁵ is substituted, it is substituted with 1-3 R⁹;        -   each R⁹ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO², —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR₂₁C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl;    -   R⁶ is hydrogen, C₁-C₆ alkyl or C₁-C₆ haloalkyl;    -   or R⁵ and R⁶ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹³;        -   each R¹³ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   R⁷ is hydrogen, unsubstituted or substituted cycloalkyl,        unsubstituted or substituted heterocycloalkyl, unsubstituted or        substituted aryl, unsubstituted or substituted heteroaryl,        unsubstituted or substituted —C₁-C₆-alkylene-cycloalkyl, or        —C(═O)R¹¹;        -   R¹¹ unsubstituted phenyl, or phenyl substituted by 1-3 R¹²;            -   each R¹² is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalky, unsubstituted or substituted aryl,                unsubstituted or substituted heteroaryl, unsubstituted                or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted                or substituted —C₁-C₆-alkylene-heterocycloalklyl,                unsubstituted or substituted —C₁-C₆-alkylene-aryl, or                unsubstituted or substituted —C₁-C₆-alkylene-heteroaryl;    -   R⁸ is hydrogen, C₁-C₆alkyl or C₁-C₆ haloalkyl;    -   or R⁷ and R⁸ are taken together with the N atom to which they        are attached to form an unsubstituted or substituted        N-containing heterocycle; wherein if the heterocycle is        substituted, it is substituted by 1-3 R¹⁰;        -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   each R₂₀ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted        C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl;    -   or two R²¹on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R², R³, R⁴, R⁷, R⁹, R¹⁰, R¹², R¹³, R²⁰, or        R²¹is substituted, substituents on the R², R³, R⁴, R⁷, R⁹, R¹⁰,        R¹², R¹³, R²⁰, or R²¹are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —C(═O)NR²²R²², —C(═O)NR²²—OR²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, monocyclic heterocycloalkyl substituted with a        R²³, phenyl, benzyl, 5-membered heteroaryl, and 6-membered        heteroaryl; or two substituents on the same carbon atom are        taken together to form a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³is independently selected from C₁-C₆ alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, having the structure of Formula (VI);

wherein:

-   -   X¹ and X² are independently N or CH;    -   X³ is N or CR³;        -   R³ is hydrogen, —CN, or -L-Ar,    -   X⁴ is N or CR⁴;        -   R⁴ is hydrogen, or -L-Ar;    -   wherein one of X³ and X⁴ is C-L-Ar;        -   L is —NH—, —O—, —S—, —C₁-C₂ alkylene-, or            -heterocycloalkylene-C(═O)—;        -   Ar is substituted or unsubstituted phenyl or substituted or            unsubstituted 5- or 6-membered heteroaryl; wherein when Ar            is substituted, it is substituted with 1-3 R⁶;            -   each R⁶ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)²NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —(C₁-C₄                alkylene)-C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl, or                unsubstituted or substituted heteroaryl;            -   or two R⁶ on adjacent atoms are taken together with the                atoms to which they are attached to form an                unsubstituted or substituted cycloalkyl, unsubstituted                or substituted heterocycloalkyl, unsubstituted or                substituted aryl, or unsubstituted or substituted                heteroaryl;    -   each R⁵ is independently hydrogen, halogen, —CN, —OH, —OR²⁰,        —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,        —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,        —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,        —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted        C₁-C₆alkyl, unsubstituted or substituted C₂-C₆ alkenyl,        unsubstituted or substituted C₂-C₆ alkynyl, unsubstituted or        substituted cycloalkyl, unsubstituted or substituted        heterocycloalkyl, unsubstituted or substituted aryl, or        unsubstituted or substituted heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹ is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        or unsubstituted or substituted heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁵, R⁶, R²⁰, or R²¹is substituted, substituents        on the R⁵, R⁶, R²⁰, or R²¹are independently selected at each        occurrence from halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³,        —OC(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,        —NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²R²², C₁-C₆        alkyl, C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and        6-membered heteroaryl; or two substituents on the same carbon        atom are taken together to form a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³is independently selected from C₁-C₆alkyl, C₃-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

wherein:

-   -   X¹ is —S—, —O—, or —NR¹—;        -   R¹ is hydrogen, unsubstituted or substituted C₁-C₆ alkyl,            unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or            substituted C₂-C₆ alkynyl, unsubstituted or substituted            cycloalkyl, unsubstituted or substituted heterocycloalkyl,            unsubstituted or substituted aryl, or unsubstituted or            substituted heteroaryl; wherein when R¹ is substituted, it            is substituted by 1-3 R⁷;        -   each R⁷ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²¹, —OC(═O)R²⁰,            —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted cycloalkyl, unsubstituted or substituted            heterocycloalkyl, unsubstituted or substituted aryl, or            unsubstituted or substituted heteroaryl;    -   X² is N or CR²;        -   R² is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl; wherein when R² is substituted, it is            substituted by 1-3 R⁸;        -   each R⁸ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆alkyl, unsubstituted or            substituted cycloalkyl, unsubstituted or substituted            heterocycloalkyl, unsubstituted or substituted aryl, or            unsubstituted or substituted heteroaryl;    -   X³ is N or CR³; wherein X² and X³ are not both N;        -   R³ is hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,            —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰,            —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, unsubstituted or substituted            heteroaryl, unsubstituted or substituted            —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted            —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or            substituted —C₁-C₆-alkylene-aryl, or unsubstituted or            substituted —C₁-C₆-alkylene-heteroaryl; wherein when R³ is            substituted, it is substituted by 1-3 R⁹;            -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)₂R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl,                unsubstituted or substituted heteroaryl, unsubstituted                or substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted                or substituted —C₁-C₆-alkylene-heterocycloalkyl,                unsubstituted or substituted —C₁-C₆-alkylene-aryl, or                unsubstituted or substituted —C₁-C₆-alkylene-heteroaryl;    -   Ar is a 6-membered aromatic ring comprising 0-2 nitrogen atoms;    -   each R⁴ is independently hydrogen, halogen, —CN, —OH, —OR⁵, —SH,        —SR⁵, —NO₂, —NR⁶R⁶, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)R⁵,        —S(═O)₂NR⁶R⁶, —C(═O)R⁵, —OC(═O)R⁵, —C(═O)OR⁶, —OC(═O)OR⁶,        —C(═O)NR⁶R⁶, —OC(═O)NR⁶R⁶, —NR⁶C(═O)NR⁶R⁶, —NR⁶C(═O)R⁵,        —NR⁶C(═O)OR⁶, unsubstituted or substituted C₁-C₆alkyl,        unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or        substituted C₂-C₆ alkynyl, unsubstituted or substituted        cycloalkyl, unsubstituted or substituted heterocycloalkyl,        unsubstituted or substituted aryl, unsubstituted or substituted        heteroaryl, unsubstituted or substituted        —C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or substituted        —C₁-C₆-alkylene-aryl, or unsubstituted or substituted        —C₁-C₆-alkylene-heteroaryl;        -   each R⁵ is independently selected from unsubstituted or            substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆            alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,            unsubstituted or substituted cycloalkyl, unsubstituted or            substituted heterocycloalkyl, unsubstituted or substituted            aryl, or unsubstituted or substituted heteroaryl; wherein if            R⁵ is substituted, it is substituted by 1-3 R¹⁰;            -   each R¹⁰ is independently halogen, —CN, —OH, —OR²⁰, —SH,                —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,                —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰,                —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,                —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,                unsubstituted or substituted C₁-C₆ alkyl, unsubstituted                or substituted C₂-C₆ alkenyl, unsubstituted or                substituted C₂-C₆ alkynyl, unsubstituted or substituted                cycloalkyl, unsubstituted or substituted                heterocycloalkyl, unsubstituted or substituted aryl, or                unsubstituted or substituted heteroaryl;        -   each R⁶is independently selected from hydrogen,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₁-C₆ alkenyl, unsubstituted or substituted            C₁-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl; wherein if R⁶ is substituted, it is substituted            by 1-3 R¹¹;        -   each R¹¹ is independently halogen, —CN, —OH, —OR²⁰, —SH,            —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,            —S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)R²¹,            —OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹,            —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,            unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or            substituted C₂-C₆ alkenyl, unsubstituted or substituted            C₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl,            unsubstituted or substituted heterocycloalkyl, unsubstituted            or substituted aryl, or unsubstituted or substituted            heteroaryl;    -   n is 0-4,    -   each R²⁰ is independently selected from unsubstituted or        substituted C₁-C₆ alkyl, unsubstituted or substituted C₂-C₆        alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   each R²¹is independently selected from hydrogen, unsubstituted        or substituted C₁-C₆ alkyl, unsubstituted or substituted C₁-C₆        alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,        unsubstituted or substituted cycloalkyl, unsubstituted or        substituted heterocycloalkyl, unsubstituted or substituted aryl,        unsubstituted or substituted heteroaryl, unsubstituted or        substituted —C₁-C₆-alkylene-cycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or        substituted —C₁-C₆-alkylene-aryl, or unsubstituted or        substituted —C₁-C₆-alkylene-heteroaryl;    -   or two R²¹ on the same N atom are taken together with the N atom        to which they are attached to form an unsubstituted or        substituted N-containing heterocycle;    -   wherein when any R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰, or R²¹is        substituted, substituents on the R⁴, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R²⁰,        or R²¹are independently selected at each occurrence from        halogen, —CN, —NO₂, —OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²²,        —NR²²R²², —NR²²C(═O)R²³, —NR²²C(═O)OR²², —SR²², —S(═O)R²³,        —SO₂R²³, —SO₂NR²²R²², C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        hydroxyalkyl, monocyclic cycloalkyl, monocyclic        heterocycloalkyl, phenyl, benzyl, benzyl substituted with        phenyl, 5-membered heteroaryl, and 6-membered heteroaryl; or two        substituents on the same carbon atom are taken together to form        a C═O or C═S;        -   each R²²is independently selected from hydrogen, C₁-C₆            alkyl, C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered            heteroaryl, and 6-membered heteroaryl;        -   or two R²²groups are taken together with the N atom to which            they are attached to form a N-containing heterocycle; and        -   each R²³is independently selected from C₁-C₆ alkyl, C₁-C₆            cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and            6-membered heteroaryl.

In some cases, the compound for modulating DUX4 activity is selectedfrom a compound listed below.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 18 or

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 20 or 21.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or is pharmaceutically acceptablesalt thereof, selected from a compound provided in FIG. 22 or 23.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 24 or 25.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 26 or 27.

In some embodiments, this disclosure provides a method for modulatingDUX4 activity (e.g., directly or vicariously) in a subject in needthereof comprising administering to the subject in need thereof acomposition comprising a compound, or a pharmaceutically acceptable saltthereof, selected from a compound provided in FIG. 28 or 29. Anotherembodiment provides a method for modulating DUX4 activity wherein themodulation of DUX4 activity is inhibition of DUX4 activity.

Certain Definitions

As used herein, the term “or” is used to refer to a nonexclusive or,such as “A or B” includes “A but not B,” “B but not A,” and “A and B,”unless otherwise indicated.

As used herein, the term “about” when referring to a number or anumerical range means that the number or numerical range referred to isan approximation within experimental variability (or within statisticalexperimental error), and thus the number or numerical range may varyfrom, for example, between 1% and 15% of the stated number or numericalrange. In some embodiments, the term “about” refers to ±10%, of a statednumber or value,

As used herein, the terms “treat,” “ameliorate,” “treatment,” and“treating” are used interchangeably, These terms refer to an approachfor obtaining beneficial or desired results including, but are notlimited to, therapeutic benefit and/or a prophylactic benefit. Bytherapeutic benefit is meant eradication or amelioration or improvementof the underlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration or improvement of one ormore of the physiological symptoms associated with the underlyingdisorder such that an improvement is observed in the patient,notwithstanding that the patient can still be afflicted with theunderlying disorder. For a prophylactic benefit, a compound providedherein may be administered to a patient at risk of developing aparticular disease, or to a patient reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made.

As used herein, in general, “a”, “an” or “the” includes both single andplural references, unless dictated otherwise by context. For example, “acompound may include a single compound or a plurality of” compounds,unless dictated otherwise by context,

The term “C_(x-y)” or “C_(x)-C_(y)” when used in conjunction with achemical moiety, such as alkyl, alkenyl, or alkynyl is meant to includegroups that contain from x toy carbons in the chain. For example, theterm “C_(x-y) alkyl” refers to substituted or unsubstituted saturatedhydrocarbon groups, including straight-chain alkyl and branched-chainalkyl groups that contain from x to y carbons in the chain. The terms“C_(x-y) alkenyl” and “C_(x-y) alkynyl” refer to substituted orunsubstituted straight-chain or branched-chain unsaturated hydrocarbongroups that contain at least one double or triple bond respectively.Unless stated otherwise specifically in the specification, a C_(x-y)alkyl, C_(x-y) alkenyl, or C_(x-y) alkynyl is optionally substituted byone or more substituents such as those substituents described herein.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring inwhich each atom of the ring is a carbon atom. Carbocycle may include 3-to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle maybe selected from saturated, unsaturated, and aromatic rings. In someembodiments, the carbocycle is an aryl, In some embodiments, thecarbocycle is a cycloalkyl. In some embodiments, the carbocycle is acycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g.,phenyl, may be fused to a saturated or unsaturated ring, e.g.,cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated,unsaturated and aromatic bicyclic rings, as valence permits, areincluded in the definition of carbocyclic. Exemplary carbocycles includecyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, iridanyl, andnaphthyl. Unless stated otherwise specifically in the specification, acarbocycle is optionally substituted by one or more substituents such asthose substituents described herein.

“Aryl” refers to a hydrocarbon ring system moiety comprising 6 to 18carbon atoms and at least one aromatic ring. For purposes of thisinvention, the aryl moiety is a monocyclic, bicyclic, tricyclic, ortetracyclic ring system, which may include fused or bridged ring systemsAryl moieties include, but are not limited to, aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. Unless stated otherwise specifically in the specification,the term “aryl” is meant to include aryl groups that are optionallysubstituted.

“Heterocycle” refers to a saturated, unsaturated or aromatic ringcomprising one or more heteroatoms Exemplary heteroatoms include N, O,Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclicrings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridgedrings. Each ring of a bicyclic heterocycle may be selected fromsaturated, unsaturated, and aromatic rings. The heterocycle may beattached to the rest of the molecule through any atom of theheterocycle, valence permitting, such as a carbon or nitrogen atom ofthe heterocycle. In some embodiments, the heterocycle is a heteroaryl,In some embodiments, the heterocycle is a heterocycloalkyl In anexemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to asaturated or unsaturated ring, e.g., cyclohexane, cyclopentane, orcyclohexene.

“Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprisesat least one heteroatom wherein each heteroatom may be independentlyselected from N, O, and S. As used herein, the heteroaryl ring may beselected from monocyclic or bicyclic and fused or bridged ring systemsrings wherein at least one of the rings in the ring system is aromatic,it contains a cyclic, delocalized (4n+2) π-electron system in accordancewith the Hückel theory. The heteroatom(s) in the heteroaryl may beoptionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the heteroaryl, valence permitting,such as a carbon or nitrogen atom of the heteroaryl. Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindoiyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b],[1,4]dioxepinyl, benzo[b],[1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryls as defined above whichare optionally substituted by one or more substituents such as thosesubstituents described herein.

Compounds of the present disclosure also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having, the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates).conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantly,found in nature. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scopeof the present disclosure. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may of certain therapeutic advantages, such asincreased in half-life and/or exposure, or may provide a compound usefulfor investigating in vivo routes of drug elimination and metabolism.isotopically-enriched compounds may be prepared by conventionaltechniques well known to those skilled in the art.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E-form (or cis- or trans-form)Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, chemical entities described hereinare intended to include all Z-, E- and tautomeric forms as well.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the structure. Itwill be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cvclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic. compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituerits of organic. compoundsdescribed herein which satisfy the valences of the heteroatoms.Substituents can include any substituents described herein, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, to sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, aheterocycloalkyl, an aromatic and heteroaromatic moiety. In someembodiments, substituents may include any substituents described herein,for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano (—CN), nitro(—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂), —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,and heteroarylalkyl any of which may be optionally substituted by alkyl,alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl,oxo (═O), thioxo (—S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—H), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);wherein each R^(a) is independently selected from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein eachR^(a), valence permitting, may be optionally substituted with alkyl,alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(═O), thioxo (—S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);and wherein each R^(b) is independently selected from a direct bond or astraight or branched alkaline, alkenylene, or alkynylene chain, and eachR^(c) is a straight or branched alkylene, alkenylene or alkynylenechain.

It will be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to a“heteroaryl” group or moiety implicitly includes both substituted andunsubstituted variants.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., a compound of Table 1, FIGS. 1-5 orcompound of Formula (I)-(VII)). Thus, the term “prodrug” refers to aprecursor of a biologically active compound that is pharmaceuticallyacceptable. in sonic aspects, a prodrug is inactive when administered toa subject but is converted in vivo to an active compound, for example,by hydrolysis. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9,21-24 (Elsevier, Amsterdam); Higuchi, T., et al., “Pro-drugs as NovelDelivery Systems,” (1987) A.C.S. Symposium Series, Vol. 14, andBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press) each of which isincorporated in full by reference herein. The term “prodrugs” is alsomeant to include any covalently bonded carriers, which release theactive compound in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of an active compound, as described herein, aretypically prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either: nroutine manipulation or in vivo, to the parent active compound Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

The compounds of the current disclosure, or their pharmaceuticallyacceptable salts may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat are defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)- for amino acids. The present invention is meant toinclude all such possible isomers, as well as their racemic andoptically pure forms. A “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures, which are not interchangeable. The presentdisclosure contemplates various stereoisomers and mixtures thereof andincludes “enantiomers,” which refers to two stereoisomers whosemolecules are nonsuperimposeable mirror images of one another. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)- isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, for example, chromatography and fractionalcrystallization. Conventional techniques for the preparation/isolationof individual enantiomers include chiral synthesis from a suitableoptically pure precursor or resolution of the racemate (or the racemateof a salt or derivative) using, for example, chiral high pressure liquidchromatography (HPLC). When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

When desired, the (R)- and (S)-isomers of the compounds of the presentdisclosure, if present, may be resolved by methods known to thoseskilled in the an, for example by formation of diastereoisomeric saltsor complexes which may be separated, for example, by crystallization;via formation of diasteroisomeric derivatives which may be separated,for example, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by convening one enantiomer to theother by asymmetric transformation.

Compounds may be dosed in their enantiomerically pure form. In someexamples, the compound has an enantiomeric excess greater than about50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99%. Compounds may bedosed in their diasteriomerically pure form. In some examples, thecompound has a diasteriomeric excess greater than about 50%, 60%, 70%,80%, 90%, 95%, 96%, 97%, 98%, or 99%.

Stereocenters may be defined using the Cahn-Ingold-Prelog priorityrules. Compounds may have stereocenters in the R-configuration,Compounds may have stereocenters in the S-configuration.

Therapeutic Agent Formulations

A pharmaceutical composition (e.g., for oral administration or forinjection, infusion, buccal delivery, subcutaneous delivery,intramuscular delivery, intraperitoneal delivery, sublingual delivery,sub-dermao, or other method) may be in the form of a liquid. A liquidpharmaceutical composition may include, for example, one or more of thefollowing: a sterile diluent such as water, saline solution, preferablyphysiological saline, Ringer's solution, isotonic sodium chloride, fixedoils that may serve as the solvent or suspending medium, polyethyleneglycols, glycerin, propylene glycol or other solvents; antibacterialagents; antioxidants, chelating agents; buffers and agents for theadjustment of tonicity such as sodium chloride or dextrose. A parenteralcomposition can be enclosed in ampoules, disposable syringes or multipledose vials made of glass or plastic. The use of physiological saline ispreferred, and an injectable pharmaceutical composition is preferablysterile. In another embodiment, for treatment of an ophthalmologicalcondition or disease, a liquid pharmaceutical composition may be appliedto the eye in the form of eye drops. A liquid pharmaceutical compositionmay be delivered orally.

For oral formulations, at least one of the compounds or agents describedherein may be used alone or in combination with appropriate additives tomake tablets, powders, granules or capsules, and if desired, withdiluents, buffering agents, moistening agents, preservatives, coloringagents, and flavoring agents. The compounds or agents may be formulatedwith a buffering agent to provide for protection of the compound fromlow pH of the gastric environment and/or an enteric coating. A compoundincluded in a pharmaceutical composition may be formulated for oraldelivery with a flavoring agent, in a liquid, solid or semi-solidformulation and/or with an enteric coating). In some cases, thecompounds of this disclosure may be solubilized and encapsulated (e.g.,in a liposome or a biodegradable polymer), or used in the form ofmicrocrystals coated with an appropriate nontoxic lipid.

A pharmaceutical composition comprising any one of the compounds oragents described herein may be formulated for sustained or slow release(also called timed release or controlled release). Such compositions maygenerally be prepared using suitable technology and administered by, forexample, oral, rectal, intradermal, or subcutaneous implantation, or byimplantation at the desired target site. Sustained-release formulationsmay contain the compound dispersed in a carrier matrix and/or containedwithin a reservoir surrounded by a rate controlling membrane. Excipientsfor use within such formulations are biocompatible, and may also bebiodegradable; preferably the formulation provides a relatively constantlevel of active component release. Non-limiting examples of excipientsinclude water, alcohol, glycerol, chitosan, alginate, chondroitin,Vitamin E, mineral oil, and dimethyl sulfoxide (DMSO). The amount ofcompound contained within a sustained release formulation depends uponthe site of implantation, the rate and expected duration of release, andthe nature of the condition, disease or disorder to be treated orprevented.

Some compounds may exhibit polymorphism. It is to be understood that thepresent disclosure encompasses any racemic, optically-active,polymorphic, or stereoisomeric form, or mixtures thereof, of a compoundof the disclosure, which possesses the useful properties describedherein, it being well known in the art how to prepare optically activeforms (for example, by resolution of the racemic form byrecrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase).

The present disclosure further provides salts of any compound describedherein. The term “salt” or “pharmaceutically acceptable salt” refers tosalts derived from a variety of organic and inorganic counter ions wellknown in the art. Salts include, for example, acid-addition salts andbase-addition salts. The acid that is added to a compound to form anacid-addition salt can be an organic acid or an inorganic acid.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, and the like. A base that is addedto a compound to form a base-addition salt can be an organic base or aninorganic base. In some cases, a salt can be a metal salt. In somecases, a salt can be an ammonium salt. Inorganic bases from which saltscan be derived include, for example, sodium, potassium, lithium,ammonium, calcium, mapnesium, iron, zinc, copper, magnesium, aluminum,and the like. Organic bases from which salts can be derived include, forexample, primary, secondary, and tertiary amines, substituted amines.Including naturally occurring substituted amines, cyclic amines, basicion exchange resins, and the like.

Acid addition salts can arise from the addition of an add to a compounddescribed herein. In some cases, the acid can be organic. In some cases,the acid can be inorganic. Non-limiting examples of suitable acidsinclude hydrochloric acid, hydrobromic acid, hydroiodic acid, nitricacid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid,nicotinic acid, isonicotinic acid, lactic acid, salicylic acid,4-aminosalicylic acid, tartaric acid, ascorbic acid, gentisinic acid,ginconic acid, glucaronic acid, saccaric acid, formic acid, benzoicacid, glutainic acid, pantothenic acid, acetic acid, propionic acid.butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid,maleic acid, hydroxymaleic acid, methylinaleic acid, glycolic acid,malic acid, cinnamic acid, mandelic acid, 2-phenoxybenzoic acid,2-acetoxybenzoic acid, embonic acid, phenylacetic acid,N-cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid p-toluenesulfonic acid, 2-hydroxyethanesuIfonicacid, ethane-1,2-disulfonic acid, 4-methylbenzenesullonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,2-phosphoglyceric acid, 3-phosphoglyceric acid, glucose-6-phosphoricacid. and an amino acid.

Non-limiting examples of suitable acid addition salts include ahydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitratesalt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt,a hydrogen phosphate salt, a dihydrofuran phosphate salt, a carbonatesalt, a bicarbonate salt, a nicotinate salt, an isonicotinate salt, alactate salt, a salicylate salt, a 4-aminosalicylate salt, a tartratesalt, an ascorbate salt, a gentisinate salt, a gluconate salt, aglucuronate salt, a saccarate salt, a formate salt, a benzoate salt, aglutamate salt, a pantothenate salt, an acetate salt, a propionate salt,a butyrate salt, a fumarate salt, a succinate salt, a citrate salt, anoxalate salt, a maleate salt, a hydroxymaleate salt, a methylmaleatesalt, a glycolate salt, a malate salt, a cinnamate salt, a mandelatesalt, a 2-phenoxybenzoate salt, a 2-acetoxybenzoate salt, an embonatesalt, a phenylacetate salt, an N-cyclohexylsulfamate salt, amethanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt,a p-toluenesulfonate salt, a 2-hydroxyethanesulfonate salt, anethane-1,2-disulfonate salt, a 4-methylbenzenesulfonate salt, anaphthalene-2-sulfonate salt, a naphthalene-1,5-disulfonate salt, a2-phosphoglycerate salt, a 3-phosphoglycerate salt, aglucose-6-phosphate salt, and an amino acid salt.

Metal salts can arise from the addition of an inorganic base to acompound described herein The inorganic base consists of a metal cationpaired with a basic counterion, such as, for example, hydroxide,carbonate, bicarbonate, or phosphate. The metal can be an alkali metal,alkaline earth metal, transition metal, or main group metal.Non-limiting examples of suitable metals include lithium, sodium,potassium, caesium, cerium, magnesium, manganese, iron, calcium,strontium, cobalt, titanium, aluminum, copper, cadmium, and zinc.

Non-limiting examples of suitable metal salts include a lithium salt, asodium salt, a potassium salt, a caesium salt, a cerium salt, amagnesium salt, a manganese salt, an iron salt, a calcium salt, astrontium salt, a cobalt salt, a titanium salt, an aluminum salt, acopper salt, a cadmium salt, and a zinc salt.

Ammonium salts can arise from the addition of ammonia or an organicamine to a compound described herein. Non-limiting examples of suitableorganic amities include triethyl amine, diisopropyl amine, ethanolamine, diethanol amine, triethanol amine, morpholine,N-methylmorpholine, piperidine. N-methylpiperidine, N-ethylpiperidine,dibenzyl amine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole,pyrazine, pipyrazine, ethylenediamine, N,N′-dibenzylethylene diamine,procaine, chloroprocaine, choline, dicyclohexyl amine, andN-methylglucamine.

Non-limiting examples of suitable ammonium salts can be a triethyl aminesalt, a diisopropyl amine salt, an ethanol amine salt, a diethanol aminesalt, a triethanol amine salt, a morpholine salt, an N-methylmorpholinesalt, a piperidine salt, an N-methylpiperidine salt, anN-ethylpiperidine salt, a dibenzyl amine salt, a piperazine salt, apyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt,a pyrazine salt, a pipyrazine salt, an ethylene diamine salt, anN,N′-dibenzylethylene diamine salt, a procaine salt, a chloroprocainesalt, a choline salt, a dieyclohexyl amine salt, and a N-methylglucaminesalt.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions of thedisclosure is contemplated Supplementary active ingredients can al alsobe incorporated into the compositions.

The term “pharmaceutically acceptable excipient” is intended to includevehicles and carriers capable of being co-administered with a compoundto facilitate the performance of its intended function. The use of suchmedia for pharmaceutically active substances is well known in the artExamples of such vehicles and carriers include solutions, solvents,dispersion media, delay agents, emulsions and the like. Any otherconventional carrier suitable for use with the multi-binding compoundsalso falls within the scope of the present disclosure,

In making the compositions of this disclosure, the active ingredient canbe diluted by an excipient. Some examples of suitable excipients includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicatemicrocrystalline cellulose, PEG, polyvinylpyrrolidone, cellulose, water,sterile saline, syrup, and methyl cellulose. The formulations canadditionally include: lubricating agents such as talc, magnesiumstearate, and mineral oil; wetting agents; emulsifying and suspendingagents; preserving agents such as methyl- and propylhydroxy-benzoates;sweetening agents; and flavoring agents. The compositions of thedisclosure can be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures known in the art.

In a sonic cases, the pharmaceutical compositions described herein maycomprise an excipient that can provide long term preservation, bulk up aformulation that contains potent active ingredients, facilitate drugabsorption, reduce viscosity, add flavoring, or enhance the solubilityof the pharmaceutical composition. Non-limiting examples of excipientscan include anti-adherents, binders (e.g , sucrose, lactose, starches,cellulose, gelatin, or polyethylene glycol), coatings (e.g.,hydroxypropyl methyl cellulose or gelatin), disintegrants, dyes, flavors(e.g., mint, peach, raspberry, or vanilla), glidants, lubricants,preservatives (e.g., acids, esters, phenols, mercurial compounds, orammonium compounds), sachems, or vehicles (e.g., petroleum or mineraloil).

The pharmaceutical compositions disclosed herein may be any type offormulation including solid formulations. In some cases the solidformulation (or other type of formulation) comprises at least 0.01 mg,0.1 mg, 1 mg, 2 mg,1 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of acompound provided in FIGS. 1-5, or a compound of any one of Formulas(I)-(VII).

In some cases, the liquid formulation may comprise a compound providedin FIGS. 1-5, or a compound of any one of Formulas (I)-(VII) of at least0.1 mg/ml, 1 mg/ml, 2 mg/ml, 3 mg/ml, 4 mg/ml, 5 mg/ml, 6 mg/ml, 7mg/ml, 8 mg/ml, 9 mg/ml, 10 mg/ml, 20 mg/ml, 30 mg/ml, 40 mg/ml, 50mg/ml, 60 mg/ml, 70 mg/ml, 80 mg/ml, 90 mg/ml, 100 mg/ml, 150 mg/ml, 200mg/ml, 250 mg/ml, 300 mg/ml, 350 mg/ml, 400 mg/ml, 450 mg/ml, 500 mg/ml,550mg/ml, 600 mg/ml, 650 mg/ml, 700 mg/ml, 750 mg/ml, 800 mg/ml, 850mg/ml, 900 mg/ml, 950 mg/ml, or 1000 mg/ml.

In some cases, a pharmaceutical composition or formulation describedherein may comprise a combination of different agents. In some cases, apharmaceutical composition described herein may comprise at least 2agents, at least 3 agents, at least 4 agents, at least 5 agents, or moreagents.

Kits

In some cases, the pharmaceutical compositions disclosed herein may beassembled into kits. In some cases, the kit can comprise one or morecompounds provide herein. In some cases, the kit may also compriseinstructions for use. The kit may also comprise vials, tubes, needles,packaging, or other material.

Kits with unit doses of one or more of the compounds described herein,usually in oral or injectable doses, are provided. Such kits may includea container containing the unit dose, an informational package insertdescribing the use and attendant benefits of the drugs in treating thedisease, and optionally an appliance or device for delivery of thecomposition.

The kit may further comprise any device suitable for administration ofthe composition. For example, a kit comprising an injectable formulationof pharmaceutical compositions may comprise a needle suitable forsubcutaneous administration and an alcohol wipe for sterilization of theinjection site.

In some cases, kits may be provided with instructions. The instructionsmay be provided in the kit or they may be accessed electronically (e.g.,on the World Wide Web). The instructions may provide information on howto use the compositions of the present disclosure. The instructions mayfurther provide information on how to use the devices of the presentdisclosure. The instructions may provide information on how to performthe methods of the disclosure. In some cases, the instructions mayprovide dosing information. The instructions may provide druginformation such as the mechanism of action, the formulation of thedrug, adverse risks, contraindications, and the like. In some cases, thekit is purchased by a physician or health care provider foradministration at a clinic or hospital. In some cases, the kit ispurchased by a laboratory and used for screening candidate compounds.

Therapeutic Agent Administration

The compounds of the current disclosure may be administered to a subjectwith a muscle disease or deficiency in order to treat the muscle diseaseor deficiency. In sonic cases the compounds may be Src, Tie, Abl, Trk,Flt, Yes, FAK, and/or PRKDC inhibitors. In some cases, the compound maybe rebastinib or analog or salt thereof In some cases, the compound maybe a compound of FIGS. 1-5, or a compound of any one of Formulas(I)-(VII).

The compounds of the current disclosure may be administered by any ofthe accepted modes of administration of agents haying similar utilities,for example, by cutaneous, oral, topical, intradermal, intrathecal,intravenous, subcutaneous, intramuscular, intra-articular, intraspinalor spinal, nasal, epidural, rectal, vaginal, or transdermal/transmucosalroutes. The most suitable route will depend on the nature and severityof the condition being treated. Subcutaneous, intradermal andpercutaneous injections can be routes for the compounds of thisdisclosure. Sublingual administration may be a route of administrationfor compounds of this disclosure, intravenous administration may be aroute of administration for compounds of this disclosure In a particularexample, the pharmaceutical composition provided herein may beadministered to a patient orally.

In some aspects, the methods provided herein involve administering acompound or agent for a period of time to a subject. followed bywithdrawal of the compound or agent. For example, the compound or agentmay be administered for 24 hours or less, followed by withdrawal of thecompound or agent. In some cases, DUX4 expression remains inhibitedafter withdrawal of the compound or agent. For example, DUX4 expressionmay remain inhibited for at least 1 day, at least 2 days, at least 3days, at least 4 days, at least 5 days, at least 6 days, at least 7days, at least 8 days, at least 9 days, at least 10 days or greater than10 days after withdrawal of the compound or agent in some cases, thecompound or agent is administered one or more additional times afterwithdrawal.

In some cases, the compound or agent is administered as a stand-aloneagent. In other cases, the compound or agent is co-administered with oneor more additional therapies (e.g.. drug). in some cases, the compoundor agent is co-administered (or co-formulated) with a cell-based therapyfor the treatment of a muscular or neuromuscular dystrophy (e,g,, FSHD).

The compounds of the present disclosure, or their pharmaceuticallyacceptable salts, are generally administered in a therapeuticallyeffective amount. The term “therapeutically effective amount” maygenerally refer to the amount (or dose) of a compound or other therapythat is minimally sufficient to prevent, reduce, treat or eliminate acondition, or risk thereof, when administered to a subject in need ofsuch compound or other therapy. In some instances the term“therapeutically effective amount” may refer to that amount of compoundor other therapy that is sufficient to have a prophylactic effect whenadministered to a subject. The therapeutically effective amount mayvary; for example, it may vary depending upon the subject's condition,the weight and age of the subject, the severity of the diseasecondition, the manner of administration and the like, all of which ma bedetermined by one of ordinary skill in the art. The amount of thecompound actually administered may be determined by a physician orcaregiver, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, thecompound administered and its relative activity, the age, weight, theresponse of the individual patient, the severity of the patient'ssymptoms, and. the like.

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas 1-VI)) to a subject or patient may comprise administering adaily dose of greater than 0 mg/m², greater than 1 mg/m², greater than 2mg/m², greater than 3 mg/m², greater than 4 mg/m², greater than 5 mg/m²,greater than 6 mg/m², greater than 7 mg/m², greater than 8 mg/m²,greater than 9 mg/m², greater than 10 mg/m², greater than 12 mg/m²,greater than 13 mg/m², greater than 14 mg/m², greater than 15 mg/m²,greater than 16 mg/m², greater than 17 mg/m², greater than 18 mg/m²,greater than 19 mg/m², greater than 20 mg/m², greater than 21 mg/m²,greater than 22 mg/m², greater than 23 mg/m², greater than 24 mg/m²,greater than 25 mg/m², greater than 26 mg/m², greater than 27 mg/m²,greater than 28 mg/m², greater than 29 mg/m², greater than 30 mg/m²,greater than 31 mg/m², greater than 32 mg/m², greater than 33 mg/m²,greater than 34 mg/m², greater than 35 mg/m², greater than 36 mg/m²,greater than 37 mg/m², greater than 38 mg/m², greater than 39 mg/m²,greater than 40 mg/m², greater than 41 mg/m², greater than 42 mg/m²,greater than 43 mg/m², greater than 44 mg/m², greater than 45 mg/m²,greater than 46 mg/m², greater than 47 mg/m², greater than 48 mg/m²,greater than 49 mg/m², greater than 50 mg/m², greater than 51 mg/m²,greater than 52 mg/m², greater than 53 mg/m², greater than 54 mg/m²,greater than 55 mg/m², greater than 56 mg/m², greater than 57 mg/m²,greater than 58 mg/m², greater than 59 mg/m², greater than 60 mg/m²,greater than 70 mg/m², greater than 80 mg/m², greater than 90 mg/m²,greater than 100 mg/m², greater than 110 mg/m², greater than 120 mg/m²,greater than 130 mg/m², greater than 140 mg/m², greater than 150 mg/m²,greater than 200 mg/m², greater than 300 mg/m², greater than 350 mg/m²,greater than 400 mg/m², greater than 450 mg/m², greater than 500 mg/m²,greater than 750 mg/m², greater than 1000 mg/m², greater than 1250mg/m², greater than 1500 mg/m², greater than 1750 mg/m², or greater than2000 mg/m² of a compound (e.g. rebastinib or a salt of analog thereof,or one or more compounds according to any of formulas I-VI)) to asubject or patient.

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI)) to a subject or patient may comprise administering adaily dose of less than 0.5 mg/m², less than 1 mg/m², less than 2 mg/m²,less than 3 mg/m², less than 4 mg/m², less than 5 mg/m², less than 6mg/m², less than 7 mg/m², less than 8 mg/m², less than 9 mg/m², lessthan 10 mg/m², 11 mg/m², less than 12 mg/m², less than 13 mg/m², lessthan 14 mg/m², less than 15 mg/m², less than 16 mg/m², less than 17mg/m², less than 18 mg/m², less than 19 mg/m², less than 20 mg/m², lessthan 21 mg/m², less than 22 mg/m², less than 23 mg/m², less than 24mg/m², less than 25 mg/m², less than 26 mg/m², less than 27 mg/m², lessthan 28 mg/m², less than 29 mg/m², less than 30 mg/m², less than 31mg/m², less than 32 mg/m², less than 33 mg/m², less than 34 mg/m², lessthan 35 mg/m², less than 36 mg/m², less than 37 mg/m², less than 38mg/m², less than 39 mg/m², less than 40 mg/m², less than 41 mg/m², lessthan 42 mg/m², less than 43 mg/m², less than 44 mg/m², less than 45mg/m², less than 46 mg/m², less than 47 mg/m², less than 48 mg/m², lessthan 49 mg/m², less than 50 mg/m², less than 51 mg/m², less than 52mg/m², less than 53 mg/m², less than 54 mg/m², less than 55 mg/m², lessthan 56 mg/m², less than 57 mg/m², less than 58 mg/m², less than 59mg/m², less than 60 mg/m², less than 70 mg/m², less than 80 mg/m², lessthan 90 mg/m², less than 100 mg/m², less than 110 mg/m², less than 120mg/m², less than 130 mg/m², less than 140 mg/m², less than 150 mg/m²,less than 200 mg/m², less than 250 mg/m², less than 300 mg/m², less than350 mg/m², less than 400 mg/m², less than 450 mg/m², less than 500mg/m², less than 750 mg/m², less than 1000 mg/m², less than 1250 mg/m²,less than 1500 mg/m², less than 1750 mg/m², or less than 2000 mg/m², ofa compound (e.g., rebastinib or a salt of analog thereof, or one or morecompounds according to any of formulas I-VI)) to a subject or patient.

In some cases. administering a compound herein (e.g., rehastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI)) to a subject or patient. may comprise administering adaily dose of the compound (or compounds) of between 1 mg/m² and 120mg/m². In some instances, the administering a compound (e.g., rebastinibor a salt of analog thereof, or one more compounds according to any offormulas I-VI)) to a subject or patient may comprise administering adaily dose of the compound or compounds of between 20 mg/m² and 100mg/m². In some instances, the administering. a compound (e.g rehastinibor a salt of analog thereof, or one or more compounds according to anyof formulas I-VI)) to a subject or patient may comprise administering adaily dose of between 30 mg/m² and 80 In some instances, theadministering a compound (e.g., rebastinib or a salt of analog thereof,or one or more compounds according to any of formulas I-VI) to a subjector patient may comprise administering a daily dose of between 40 mg/m²and 80 mg/m². In some instances, when the administering a compound(e.g., rebastinib or a salt of analog thereof, or one or more compoundsaccording to any of formulas I-VI)) to a subject or patient comprisesadministering a daily dose of between 40 mg/m² and 80 mg/m², the subjector patient is an adult. In some instances, when the administering acompound (e.g., rebastinib or a salt of analog thereof, or one or morecompounds according to any of formulas I-VI)) to a subject or patientcomprises administering a daily dose of between 40 mg/m² and 80 mg/m²,the subject or patient is a child. In some instances, the administeringa compound (e.g., rebastinib or a salt of analog thereof, or one or morecompounds according to any of formulas I-VI)) to a subject or patientmay comprise administering a daily dose of between 50 mg/m² and 80mg/m². In some instances, the administering a compound (e g., rebastinibor a salt of analog thereof, or one or more compounds according to anyof formulas I-VI)) to a subject or patient may comprise administering adaily dose of between 40 mg/m² and 60 mg/m². In some instances, theadministering a compound (e.g., rebastinib or a salt of analog thereof,or one or more compounds according to any of formulas I-VI)) to asubject or patient may comprise administering a daily dose of between 50mg/m² and 60 mg/m². In some instances, the administering a compound(e.g., rebastinib or a salt of analog thereof, or one or more compoundsaccording to any of formulas I-VI)) to a subject or patient may compriseadministering a daily dose of between 45 mg/m² and 65 mg/m².

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI)) to a subject or patient may comprise administering adaily dose of less than 150 mg, less than 140 mg, less than 130 mg, lessthan 120 mg, less than 110 mg, less than 100 mg, less than 98 mg, lessthan 96 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg,less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, lessthan 15 mg, less than 10 mg, less than 9 mg, less than 8 mg, less than 7mg, less than 6 mg, less than 5 mg, less than 4 mg, less than 3 mg, lessthan 2 mg, or less than 1 mg. In some instances, the subject or patientto which the compound herein is administered is an adult. In someinstances, the subject or patient to which the compound herein isadministered is a child.

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI)) to a subject or patient may comprise administering adaily dose of less than about 150 mg, less than about 140 mg, less thanabout 130 mg, less than about 120 mg, less than about 110 mg, less thanabout 100 mg, less than about 98 mg, less than about 96 mg, less thanabout 95 mg, less than about 90 mg, less than about 85 mg, less thanabout 80 mg, less than about 75 mg, less than about 70 mg, less thanabout 65 mg, less than about 60 mg, less than about 55 mg, less thanabout 50 mg, less than about 45 mg, less than about 40 mg, less thanabout 35 mg, less than about 30 mg, less than about 25 mg, less thanabout 20 mg, less than about 15 mg, less than about 10 mg, less thanabout 9 mg, less than about 8 mg, less than about 7 mg, less than about6 mg, less than about 5 mg, less than about 4 mg, less than about 3 mg,less than about 2 mg, or less than about 1 mg. In some instances, thesubject or patient to which the compound herein is administered is anadult.

In some instances, the subject or patient to which the compound hereinis administered is a child.

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI)) to a subject or patient may comprise administering adaily dose of greater than 150 mg, greater than 140 mg, greater than 130mg, greater than 120 mg, greater than 110 mg, greater than 100 mg,greater than 95 mg, greater than 90 mg, greater than 95 mg, greater than90 mg, greater than 85 mg, greater than 80 mg, greater than 75 mg,greater than 70 mg, greater than 65 mg, greater than 60 mg, greater than55 mg, greater than 50 mg, greater than 45 mg, greater than 40 mg,greater than 35 mg, greater than 30 mg, greater than 25 mg, greater than20 mg, greater than 15 mg, greater than 10 mg, greater than 9 mg,greater than 8 mg, greater than 7 mg, greater than 6 mg, greater than 5mg. greater than 4 mg, greater than 3 mg, greater than 2 mg, greaterthan or greater than 1 mg. In some instances, the subject or patient towhich the compound herein is administered is an adult. In someinstances, the subject or patient to which the compound herein isadministered is a child.

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI)) involves administering a dose that is selected to avoidor minimize one or more adverse events including but not limited tohematologic toxicity (e.g., anemia, myelosuppression, leukopenia,thrombocytopenia), nausea, diarrhea, vomiting, constipation,paresthesia, hypoesthesia, decreased appetite, or fatigue. In somecases, administering a compound herein (e.g., rebastinib or a salt ofanalog thereof, or one or more compounds according to any of formulasI-VI)) involves administering a dose that is selected to avoid orminimize cytotoxicity (e.g. to neurons, muscle cells, orgastrointestinal cells).

In some cases, administering a compound herein (e.g., rebastinib or asalt of analog thereof, or one or more compounds according to any offormulas I-VI) to a patient may comprise administering a daily dose of0.1 mg/m², 0.2 mg/m², 0.3 mg/m², 0.4 mg/m², 0.5 mg/m², 0.6 mg/m², 0.7mg/m², 0.8 mg/m², 0.9 mg/m², 1 mg/m², 1.1 mg/m², 1.2 mg/m², 1.3 mg/m²,1.4 mg/m², 1.5 mg/m², 1.6 mg/m², 1.7 mg/m², 1.8 mg/m², 1.9 mg/m², 2mg/m², 2.1 mg/m², 2.2 mg/m², 2.3 mg/m², 2.4 mg/m², 2.5 mg/m², 2.6 mg/m²,2.7 mg/m², 2.8 mg/m², 2.9 mg/m², 3 mg/m², 3.1 mg/m², 3.2 mg/m², 3.3mg/m², 3.4 mg/m², 3.5 mg/m², 3.6 mg/m², 3.7 mg/m², 3.8 mg/m², 3.9 mg/m²,4 mg/m², 4.1 mg/m², 4.2 mg/m², 4.3 mg/m², 4.4 mg/m², 4.5 mg/m², 4.6mg/m², 4.7 mg/m², 4.8 mg/m², 4.9 mg/m², 5 mg/m², 5.1 mg/m², 5.2 mg/m²,5.3 mg/m², 5.4 mg/m², 5.5 mg/m², 5.6 mg/m², 5.7 mg/m², 5.8 mg/m², 5.9mg/m², 6 mg/m², 6.1 mg/m², 6.2 mg/m², 6.3 mg/m², 6.4 mg/m², 6.5 mg/m²,6.6 mg/m², 6.7 mg/m², 6.8 mg/m², 6.9 mg/m², 7 mg/m², 7.1 mg/m², 7.2mg/m², 7.3 mg/m², 7.4 mg/m², 7.5 mg/m², 7.6 mg/m², 7.7 mg/m², 7.8 mg/m²,7.9 mg/m², 8 mg/m², 8.1 mg/m², 8.2 mg/m², 8.3 mg/m², 8.4 mg/m², 8.5mg/m², 8.6 mg/m², 8.7 mg/m², 8.8 mg/m², 8.9 mg/m², 9 mg/m², 9.1 mg/m²,9.2 mg/m², 9.3 mg/m², 9.4 mg/m², 9.5 mg/m², 9.6 mg/m², 9.7 mg/m², 9.8mg/m², 9.9 mg/m², 10 mg/m², 11 mg/m², 12 mg/m², 13 mg/m², 14 mg/m², 15mg/m², 16 mg/m², 17 mg/m², 18 mg/m², 19 mg/m², 20 mg/m², 21 mg/m², 22mg/m², 23 mg/m², 24 mg/m², 25 mg/m², 26 mg/m², 27 mg/m², 28 mg/m², 29mg/m², 30 mg/m², 31 mg/m², 32 mg/m², 33 mg/m², 34 mg/m², 35 mg/m², 36mg/m², 37 mg/m², 38 mg/m², 39 mg/m², 40 mg/m², 41 mg/m², 42 mg/m², 43mg/m², 44 mg/m², 45 mg/m², 46 mg/m², 47 mg/m², 48 mg/m², 49 mg/m², 50mg/m², 51 mg/m², 52 mg/m², 53 mg/m², 54 mg/m², 55 mg/m², 56 mg/m², 57mg/m², 58 mg/m², 59 mg/m², 60 mg/m², 61 mg/m², 62 mg/m², 63 mg/m², 64mg/m², 65 mg/m², 66 mg/m², 67 mg/m², 68 mg/m², 69 mg/m², 70 mg/m², 71mg/m², 72 mg/m², 73 mg/m², 74 mg/m², 75 mg/m², 76 mg/m², 77 mg/m², 78mg/m², 79 mg/m², 80 mg/m², 81 mg/m², 82 mg/m², 83 mg/m², 84 mg/m², 85mg/m², 86 mg/m², 87 mg/m², 88 mg/m², 89 mg/m², 90 mg/m², 91 mg/m², 92mg/m², 93 mg/m², 94 mg/m², 95 mg/m², 96 mg/m², 97 mg/m², 98 mg/m², 99mg/m², or 100 mg/m² of the compound.

The daily dose of the compound may be greater than 0 mg, greater than 1mg, greater than 2 mg, greater than 3 mg, greater than 4 mg, greaterthan 5 mg, greater than 6 mg, greater than 7 mg, greater than 8 mg,greater than 9 mg, greater than 10 mg, greater than 11 mg, greater than12 mg, greater than 13 mg, greater than 14 mg, greater than 15 mg,greater than 16 mg, greater than 17 mg, greater than 18 mg, greater than19 mg, greater than 20 mg, greater than 21 mg, greater than 22 mg,greater than 23 mg, greater than 24 mg, greater than 25 mg, greater than26 mg, greater than 27 mg, greater than 28 mg, greater than 29 mg,greater than 30 mg, greater than 31 mg, greater than 32 mg, greater than33 mg, greater than 34 mg, greater than 35 mg, greater than 36 mg,greater than 37 mg, greater than 38 mg, greater than 39 mg, greater than40 mg, greater than 41 mg, greater than 42 mg, greater than 43 mg,greater than 44 mg, greater than 45 mg, greater than 46 mg, greater than47 mg, greater than 48 mg, greater than 49 mg, greater than 50 mg,greater than 100 mg, greater than 150 mg, greater than 200 mg, greaterthan 300 mg, greater than 350 mg, greater than 400 mg, greater than 450mg, greater than 500 mg, greater than 750 mg, greater than lg, greaterthan 5 g, greater than 10 g, or higher.

In some cases, the daily dose of the compound may be administered in asingle dose. In some cases, the daily dose may be divided into 1, 2,3,4, 5, 6, 7, 8, 9, or 10 doses per day. For example, the daily dose canbe divided into 3 doses per day. In some cases, the daily dose may bedivided into at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,40, 45, 50, 55, or 60 infusions per hour. In some cases, each infusionof a composition comprising a drug as described herein (e g. rebastinibor on or more compounds according to any of formulas I-VII) may last forat least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5hours, 5 hours, 5.5 hours, or 6 hours.

In some cases, the daily dose of the compound may be administered in asingle dose. In some cases, the daily dose may be divided into 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 doses per day. For example, the daily dose canbe divided into 3 doses per day, In some cases, the daily dose may bedivided into at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20. 25, 30, 35,40, 45, 50, 55, or 60 infusions per hour. In some cases, each infusionof a composition comprising a drug as described. herein (e.g., 0,rebastinib or on or more compounds according to any of formulas I-VII)may last. for at least 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55minutes, 1 hour, 1.5 hours, 2 hours, 2.5 how's, 3 hours, 3.5 hours, 4hours, 4.5 hours, 5 hours, 5.5 hours, or 6 hours.

The compounds described herein may be administered to a patient one ormore times per day. in some cases, the compounds may he administered toa patient one time per day. In some cases, the compounds may beadministered to a patient at least 2 times, 3 times, 4 times 5 times, 6times, 7 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20times, 21 times, 22 times. 23 times, or 24 times per day. For example, acompound may be administered to a patient 3 times per day.

The compounds described herein may be administered to a patient for oneor more days. In some cases, the compound may be administered to apatient for one day. In some cases, the pharmaceutical composition mayhe administered to the patient for at least 2 days, at least 3 days, atleast 4 days, at least 5 days, at least 6 days, at least. I week, atleast 2 weeks, at least 3 weeks, at least 1 month, at least 2 months, atleast 3 months, at least 4 months, at least 5 months, at least 6 months,at least 7 months, at least 8 months, at least 9 months, at least 10months, at least 11 months, at least l year, at least 2 years, at least3 years, at least 4 years, at least 5 years, at least 6 years, at least7 years, at least 8 years, at least 9 years, at least 10 years, at least20 years, at least 30 years, at least 40 years, or at least 50 years. insome cases, the pharmaceutical composition may be administered to thepatient for at least 20 contiguous days, at least 28 contiguous days, atleast 40 contiguous days, at least 60 contiguous days, at least 90contiguous days, at least 100 contiguous days, or at least 200contiguous days. In some cases, the contiguous administration isnear-contiguous. For example, the administration may be for at least 28contiguous days, except for one or two days during that period which maybe skipped.

The compounds described herein may be effective over time. in somecases, the compounds may be effective for one or more days_(—) In somecases, the duration of efficacy of the compounds is over a long periodof time. In some cases, the efficacy of the compound may be greater than2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 1month. In some cases, the efficacy of the compound may be less than 2days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 1month. The compound as described herein (e.g., rebastinib or a salt ofanalog thereof, or one or more compounds according to any of formulasVI) may be administered to maintain a therapeutic serum concentrationrange within the subject or patient for an extended period of time,chronically, or indefinitely. In some embodiments, the compound isadministered to maintain a therapeutic serum concentration range forgreater than 10, greater than 15, greater than 20, greater than 25,greater than 30, greater than 45, or greater than 50 days. In someembodiments, the compound is administered to maintain a therapeuticserum concentration range for greater than 1 month, greater than 2months, greater than 3 months, greater than 4 months, greater than 5months, greater than 6 months, greater than 7 months, greater than 8months, greater than 9 months, greater than 10 months, greater than 11months, greater than 12 months, greater than 5 years, greater than 10years, greater than 15 years, greater than 20 years, greater than 30years, or longer. In some embodiments, the compound is administered tomaintain a therapeutic _muscular concentration range (e.g. therapeuticdrug concentration in skeletal muscle range) for greater than 10,greater than 15, greater than 20, greater than 25, greater than 30,greater than 45, or greater than 50 days. in some embodiments, thecompound is administered to maintain a therapeutic muscle concentrationrange for greater than 1 month, greater than 2 months, greater than 3months, greater than 4 months, greater than 5 months, greater than 6months, greater than 7 months, greater than 8 months, greater than 9months, greater than 10 months, greater than 11 months, greater than 12months, greater than 5 years, greater than 10 years, greater than 15years, greater than 20 years, greater than 30 years, or longer.

In some embodiments, the compound is administered daily for greater than10, greater than 15, greater than 20, greater than 25, greater than 30,greater than 45, or greater than 50 days. In some embodiments, thecompound is administered daily for greater than 1 month, greater than 2months, greater than 3 months, greater than 4 months, greater than 5months, greater than 6 months, greater than 7 months, greater than 8months, greater than 9 months, greater than 10 months, greater than 1.months, greater than 12 months, greater than 5 years, greater than 10years, greater than 15 years, greater than 20 years, greater than 30years, or longer. In some embodiments, the compound is administeredweekly or bi-weekly for greater than 1 month, greater than 2 months,greater than 3 months, greater than 4 months, greater than 5 months,greater than 6 months, greater than 7 months, greater than 8 months,greater than 9 months, greater than 10 months, greater than 11 months,greater than 12 months, greater than 5 years, greater than 10 years,greater than 15 years, greater than 20 years, greater than :30 years, orlonger.

In some cases, including situations when the compound (e.g., rebastinibor a salt of analog thereof, or one or more compounds according to anyof formulas I-VI) is administered for an extended period of time orchronically, DUX4 inhibition may be monitored over time. Effectiveinhibition of DUX4 activity can be monitored, for example, by periodic(e.g. every 1, 2, 3, 4, 5, 6 months) biopsy of tissue (e.g., skeletalmuscle) of the patient followed by measurement of DUX4 expression and/orby measurement of markers of DUX4 activity (e.g activation or expressionof target genes including but not limited to CCNA1, KHDC1L, LEUTX,M8D3L2, PRAMEF2, PRAMEF6, SPRYD5, TRIM43, TRIM49, ZNF296, ZSCAN4 bywestern blot, Q-PCR, RNA sequencing, or another suitable method) in thebiopsied cells or tissue. The DUX4 may be detected at the mRNA level orthe protein level, or by a functional assay. Suitable skeletal musclesfor periodic biopsy include muscles of the upper torso, deltoid muscles,or trapezius muscles. In some cases, specific cell types may beanalyzed, such as muscle cells, myoblast cells, or myotubes. In someembodiments, skeletal muscle is biopsied both before and after treatmentto provide information on the degree of inhibition of DUX4 activityprovided by the administered compound. In instances where the compounddoes not lead to complete inhibition of DUX4 activity as determined bybiopsy, the dose of the compound may be adjusted upward. Alternatively,when side effects are observed due to administration of the compound orDUX4 inhibition determined by biopsy is sufficient, the dose of thecompound may be adjusted downward. In some cases, where stableinhibition of DUX4 is detected, the dose of the compound administered tothe patient may be maintained over time.

In some embodiments, this disclosure provides a method of treating amuscular degenerative disorder in a subject in need thereof ormodulating DUX4 activity in a subject in need there of using any of thecompounds described herein (e.g. rebastinib, or a salt thereof, or acompound according, to any one of formulas or a salt thereof), whereinthe method further comprises monitoring DUX4 expression or activity in atissue of the subject following administration of the compound. In someembodiments, DUX4 expression is monitored by monitoring DUX4 mRNAexpression, DUX4 protein expression, or both DUX4 mRNA expression andDUX4 protein expression. In some cases, the method comprises taking ablood, plasma, serum or urine sample from the subject and detecting thelevel of a marker of muscle injury. In some cases, the method comprisestaking a blood, plasma, serum or urine sample from the subject anddetecting the level of creatinine kinase, aldolase, and/or muscleenzymes in the sample. In some embodiments, the method comprisesmonitoring the level of DUX4, creatinine kinase, aldolase, or muscleenzymes or any combination thereof over time, such as over two timepoints, over three time points. in cases where a marker of muscle injuryincreases or stays the same, the level of compound administered to thesubject may, in some cases, be adjusted upwards. In cases where themarker decreases over time, the level of the compound administered tothe subject may, in some cases, be maintained or adjusted downward. Insome embodiments, provided herein is a method of treating a musculardegenerative disorder in a subject in need thereof or modulating DUX4activity in a subject in need there of using any of the compoundsdescribed herein (e.g rebastinib, or a salt: thereof, or a compoundaccording to any one of formulas I-VII, or a salt thereof), wherein,following administration of the compound, the subject in need thereofexperiences a least a 10%, at least a 25%, at least a 50%, at least a75%, or at least a 100% decrease in a marker of muscle injury,creatinine kinase, and/or aldolase.

In some embodiments, DUX4 expression or activity in a subject ismonitored over time prior to administration of a compound providedherein, in order to determine whether the subject has a natural orbaseline cycle of DUX4 expression or activity. In the event such cycleis detected, the subject or patient may be monitored over time afteradministration of the compound at timepoints that approximate the samepoint in the cycle, such as the beginning of the cycle, the peak of thecycle, the nadir of the cycle, or the end of the cycle.

In certain particular embodiments, more than one compound of the currentdisclosure may be administered at a time to a subject. In someembodiments, two compounds of the current disclosure in combination makeact synergistically or additively, and either compound may be used in alesser amount than if administered alone.

Any of the compounds or agents provided herein may be administered to asubject in combination with a cell therapy. The effects of thecombination may be additive, in some cases, the effects of thecombination are synergistic. The compounds may be administered before,during or after the administration of the cell therapy. In some cases,the compounds or agents are administered separately from the celltherapy. In some cases, the cell therapy is mixed with one or more ofthe compounds. in some examples, the cell therapy may involveintroducing skeletal muscle cells into a subject and a compound providedherein is also administered into the subject in order to repress DUX4expression in vivo in skeletal muscle cells.

EXAMPLES Drug Screening Example 1—Workflow

FIG. 6 provides an example of a screening and culturing workflow forhESC-SkM assays, At Day 0, hESC-derived myoblasts are thawed into a96-well plate in myoblast medium (Genea. BioCells). On Day 2, the mediumis replaced with new myoblast medium containing 1.15 μM. Decitabine. OnDay 3, the medium is changed again, this time the new medium is MyotubeMedium (Genea BioCells) containing GBC0905 or GBC0772. On Day 7, themyotubes are analyzed. For example, the myotubes may be analyzed for MHCexpression or DUX4 expression.

Example 2—ESIID hESC-SkM Primary Screen Assay:

Immunocytochemistry—DUX4, Myosin Heavy Chain, Nuclei 100 nM GBC0905(Rebastinib) treatment of FSHD hESC-SkM results in decreased DUX4expression with no significant off-target toxicity as evidenced bymyonuclear count or Myosin. Heavy Chain area while a positive controlGBC0772 (MLN4924) inhibits myogenesis and leads to a non-specificdecrease in DUX4 and Myosin Heavy Chain expression.

Methods:

Genea049 FSHD-affected human Embryonic Stem Cells (hESCs) weredifferentiated using Genea's myogenic differentiation protocol (Caron et2015) to the myoblast stage and cryopreserved. Frozen myoblasts wereresuscitated and 4500 cells were plated into each well of a 96-wellcollagen I coated tissue culture plate in myoblast medium. After twodays of cell growth medium was changed to 100 μL per well myoblastmedium containing 1.15 μM Decitabine. After 1 day of additional growthmedium was changed to 100 μL per well myotube medium containing 100 nMGBC0772 (MLN4924) or GBC0905 (Rebastinib) or DMSO vehicle. Cells wereallowed to differentiate to myotubes for four additional days then werefixed and analyzed for quantification of DUX4 expression, Myosin HeavyChain expression, and nuclei number. Triplicate wells of each conditionwere averaged.

Results:

As illustrated in FIG. 7, treatment of Genea049 hFSC-SkM during myotubeformation with either 100 nM GBC0772 (MLN4924) GBC0905 (Rebastinib)results in decreased DUX4 expression after four days of culture WhileGBC0772 treatment also results in decreased Myosin Heavy Chainexpression and nuclei count characteristic of myogenicinhibition/toxicity, these effects are not seen in cells treated withGBC0905 (Rebastinib)t. These results indicate a specificDUX4-suppressive, pro-therapeutic effect of GBC0905 (Rebastinib)treatment.

Example 3—FSHD hESC-SkM Dose Curve Assay:

Immunocytochemistry—DUX4, Myosin Heavy Chain, Nuclei GBC0905 treatmentof FSHD hESC-SkM results in decreased DUX4 expression in adose-dependent manner. In contrast, treatment with myogenesis inhibitorGBC0772 decreases DUX4 and Myosin Heavy Chain Area equipotently, showingnon-specific effect.

Methods:

Genea049 FSHD-affected human Embryonic Stem Cells (hESCs) weredifferentiated using Genea's myogenic differentiation protocol (Caron etal,, 2015) to the myoblast stage and cryopreserved. Frozen myoblastswere resuscitated and 4500 cells were plated into each well of a 96-wellcollagen I coated tissue culture plate in myoblast medium. After twodays of cell growth medium was changed to 100 μL per well myoblastmedium containing 1.15 μM Decitabine. After 1 day of additional growthmedium was changed to 100 μL per well myotube medium containing GBC0772(MLN4924) or GBC0905 (Rebastinib) at concentrations ranging from 10 nM-3μM or equivolume DMSO vehicle. Cells were allowed to differentiate tomyotubes for four additional days then were fixed and analyzed forquantification of DUX4 expression, Myosin Heavy Chain expression, andnuclei number by high-content imaging. Triplicate wells of eachcondition were averaged.

Results:

As shown in FIG. 8, treatment of Genea049 hESC-SkM during myotubeformation at six concentration points for both GBC0772 (MLN4924) orGBC0905 (Rebastinib) results in dose-dependent decreased DUX4 expressionafter four days of culture. GBC0772 (MLN4924) treatment also results indecreased Myosin Heavy Chain expression and nuclei count characteristicof myogenic inhibition/toxicity at all concentrations where DUX4decrease is apparent. In contrast, effects on Myosin Heavy Chain are notseen in cells treated with GBC0905 (Rebastinib) at concentrations lowerthan 3 μM. These results indicate a specific DUX4-suppressive,therapeutic effect of GBC0905 (Rebastinib) treatment with an estimatedIC50 value of approximately 100 nM.

FIG. 9 provides representative images from the dose response experimentof example 3.

Example 4—Primary Patient Biopsy-Derived Muscle

FIG. 10 provides the workflow for assays performed with patientbiopsy-derived muscle. On Day 0, patient myoblasts are passaged in a96-well dish in primary myoblast medium (Genea BioCells). On Day 2, themedium is changed to primary myoblast medium. On Day 3, the medium ischanged to primary myotube medium containing GBC0905 On Day 5, themyotubes are analyzed.

Example 5—FSHD Primary Patient Biopsy Myotube Dose Response

2° Assay: Immunocytochemistry—DUX4, H3.X/Y (Cell Stress), Myosin heavyChain, Nuclei: GBC0905 (Rebastinib) treatment of FSHD primary patientbiopsy muscle cultures reduces clinically relevant DUX4 and H3,X/Ystress marker expression in a dose-dependent manner without yielding atoxic or myoglenic inhibitory effect.

Methods:

17MB026 primary FSHD-affected patient myoblasts (obtained from theUniversity of Rochester FSHD Biorepository) were thawed and cultured asdescribed in Rickard et al., 2015 in primary myoblast medium. Cells(6000 per well) were seeded to a collagen-I coated 96-well plate in 100μl primary myoblast medium. Medium was changed every other day untilcells reached 80% confluence followed by a switch to 100 μL per wellprimary myotube medium. GBC0905 (Rebastinib, 2 nM-5 μM dose range) orDMSO vehicle was delivered to each well. Cells were fixed and analyzedafter 2.5 days of myotube formation by immunocytochemistry andhigh-content imaging for DUX4, H3.X/Y, Myosin Heavy Chain expression andnuclei number. Five or six replicate wells were averaged per condition,

Results:

Treatment of FSHD primary patient myotubes with a 10-point dose curve ofGBC0905 (Rebastinib) results in a dose-dependent decrease of DUX4expression and a similar alleviation of cell stress mediated by H3.XTVwithout reducing Myosin Heavy Chain or nuclei count. These data indicatea DUX4-suppressive effect of GBC0905 (Rebastinib) with an IC50 value ofapproximately 100 nM.

FIGS. 11a-11d provide the dose response curves from individualexperiments performed in patient biopsy-derived muscle.

FIGS. 12 and 13 provide representative images from the dose responsestudies of GBC0905 (Rebastinib) in FSHD primary patient biopsy myotubes

Example 6—MID Primary Patient Biopsy Myotube Dose Curve: Inhibition ofCaspases 3/7 Mediated Apoptosis

2° Assay: Live Cell Imaging of Caspase 3/7 Cleavage Dye FluorescenceThrough Myotube Formation: GBC0905 (Rebastinib) rescues FSHDpatient-derived myotubes from DUX4-induced death by Caspase 3/7-mediatedapoptosis.

Methods:

17MB026 primary FSHD-affected patient myoblasts (obtained from theUniversity of Rochester FSHD Biorepository) were thawed and cultured asdescribed in Rickard et al , 2015 in primary myoblast medium. Cells(4000 per well) were seeded to a collagen-I coated 96-well plate in 100μL primary myoblast medium. Medium was changed every other day untilcells reached 80% continence followed by a switch to 100 μL per wellprimary myotube medium containing 1:5000 diluted Caspase 3/7 Green.Apoptosis Assay Reagent (Essen Bioscience). GBC0905 (Rebastinib, 10 nM-3μM range of concentrations) of or DMSO vehicle was delivered to eachwell. Cells were imaged in the phase and green channels every six hoursfor four days to quantify green intensity× area per image. Triplicatewells of each condition were averaged

Results:

As shown in FIGS. 14(a) and 14(b), treatment of FSHD primary patientmyotubes with six distinct concentrations of GBC0905 (Rebastinib)results in a dose-dependent decrease in Caspase 3/7 activation to levelsfound in unaffected primary myotube cultures, indicating an apoptosisrescue effect of OBC0905 (Rebastinib) treatment.

Example 7—FSHD Primary Patient Biopsy Myotube Dose Curve-GBC0905(Rebastinib) rescues DUX4-mediated Cell Death in a Dose Response Manner

2° Assay: Live Cell imaging of % Cell. Confluence Through MyotubeFormation GBC0905 (Rebastinib) rescues FSHD patient-derived myotubesfrom DUX4-induced cell death,

Methods:

17MB026 primary FSHD-affected patient myoblasts (obtained from theUniversity of Rochester FSHD Biorepository) were thawed and cultured asdescribed in Rickard et al., 2015 in primary myoblast medium. Cells(4000 per well) were seeded to a collagen-I coated 96-well plate in 100μL primary myoblast medium. Medium was changed every other day untilcells reached 80% confluence followed by a switch to 100 μL per wellprimary myotube medium. GBC0905 (Rebastinib, 1.0 nM-3 μM concentrationrange) or DMSO vehicle was delivered to each well. Cells were imaged inthe phase contrast channel every six hours for four days and cellconfluence in each image was quantified, Triplicate wells of eachcondition were averaged.

Results:

As shown in FIGS. 15(a) and 15(b), treatment of FSHD primary patientmyotubes with six distinct concentrations of GBC0905 (Rebastinib)results in a dose-dependent rescue of FSHD cell death as measured byretained % cell confluence through our days of myotube formation.

FIG. 16 provides representative images for GBC0905 (Rebastinib)-mediatedprotection of FSHD affected primary patient biopsy myotubes at 3concentration paints.

Example 8—FSHD Primary Patient Biopsy Myotube Dose Curve—DL X4 TargetGene and Myogenic Gene Expression

2° Assay: Nanostring Panel Transcript Analysis: GBC0905 (Rebastinib)treatment induces a concentration-dependent reduction of a suite ofreported DUX4 target genes with no negative effect on myogenic geneexpression.

Methods:

17MB026 primary FSHD-affected patient myoblasts (obtained from theUniversity of Rochester FSHD Biorepository) were thawed and cultured asdescribed in Rickard et al., 2015 in primary myoblast medium. Cells(4000 per well) were seeded to a collagen-I coated 96-well plate in 100μL primary myoblast medium. Medium was changed every other day untilcells reached 80% confluence followed by a switch to 100 μL per wellprimary myotube medium. GBC0905 (Rebastinib, 30 nM-3 μM concentrationrange) or DMSO vehicle was delivered to each well. Cells were lysedafter 3 days of myotube formation using 10 μL of iScript Buffer (Biorad)per well. The resulting lysates were frozen at −30° C. After thaw, 5 μLof each lysate was combined with a custom-designed Nanostring transcriptprobe and capture codeset. Probes were hybridized to lysates and runcartridge was loaded and run per standard protocol. Normalization andbackground subtraction were performed using the nSolver 3.0 softwareusing standard conditions DUX4 target gene and myotube marker geneexpression values were normalized to a standard set of housekeepinggenes. Duplicate wells of each condition were averaged.

Results:

As shown in FIGS. 17(a) and 17(b), treatment of FSHD primary patientmyotubes with a six-point dose curve of GBC0905 results in adose-dependent decrease of 11 DUX4-activated genes not normallyexpressed in muscle (17(a)) and does not decrease expression of queriedcharacteristic myotube genes (17(b)). This data suggests that GBC0905(Rebastinib) specifically rescues the measured gene expression effect ofDUX4 activation in FSHD muscle cells without affecting skeletal musclehealth.

According to the methods provided herein, small molecules that are knownor suspected to target networks and pathways related to FSHD may be usedto treat the disease. The small molecules may have known or suspectedtargets that are involved in Src, Lck, Fyn, Lyn., Syk, EAK, TrkA TrkB,TrkC, Tie1, Tie2, VEGFR1, VEGER2, Flt4, EGFR1FGFR.2, FGFR3, FGFR4, c-MetRon, ErbB1, ErbB2, ErbB4, EphB2EphB4, PDOFR^(a), PDGFRb, DNA-PK (orPRKDC), a compound of Table 1, FIGS. 1-5, or a compound of any one ofFormulas (I)-(VII).

Example 9 Pharmacokinetic Study and Tissue Distribution Study

In this acute pharmacokinetic study, mice were administered a singledose of GBC0905 (rebastinib) at 1 0 mg/kg or 50 mg/kg by eitherintraperitoneal or intramuscular injection formulated in Miglyol 810N:Phosal 50 PG: Polysorbate 80 (Tween 80) at 45:50:5 (V:V).Intraperitoneal injection, which provides the drug via absorption. intothe mesenteric blood supply and is thus subject to hepatic first-passmetabolism, was used to approximate oral dosings total of 96 mice wereutilized: 3 naive CD-1 male mice and 3 naïve CD-1 female mice were dosedper route of administration per 2 doses plus 3 naive CD-1 male mice and3 naïve CD-1 female mice were per route of administration per dose fortissue collection. Following administration, blood, brain, and musclesamples were collected as follows; Two blood samples were collected fromeach mouse at 2 distinct timepoints over 24 bout post-dose to include0.25, 0.5, 1, 2, 4, 8, and 24 hours. Blood samples were centrifuged toobtain plasma samples For each time point, duplicate aliquots of plasmawere transferred into an appropriately labeled sample tube containing avolume of buffer. The diluted plasma samples were stored at −20° C. forthe first 24 hours and then transferred to −80° C. 24 hours ofprocessing. Terminal brain and muscle samples were collected at 1 hourand 24 hours after administration. Tissue samples were temporarily puton dry ice and then stored at −20° C. for the first 24 hours and thentransferred to −80° C. 24 hours of collection Plasma, brain and musclesamples were analyzed for test substance quantification using a methodbased on protein precipitation followed by HPLC-MS/MS analysis withinoptimized bioanalytical method.

All mice survived to scheduled sacrifice and no adverse clinical signsoccurred during this study, Mean peak plasma concentrations occurredwithin a median time to maximum concentration (T_(max)) of 2 hours usingintraperitoneal injection or 2-4 hours with an intramuscular injection.Exposure, including mean maximum concentration (C_(max)), area under thecurve from 0-24 hours (AUC_(last)), and area under the curve to infinity(AUC_(∞)) increased with dose (Table 2) but in less than adose-proportional manner. Selected Plasma PK parameters are presented inTable 2.

FIG. 30 provides mean plasma rebastinib concentration-time profilefollowing a single administration of rebastinib by eitherintraperitoneal (IP) or intramuscular injection (IM). Blood samples wereobtained from the saphenous vein at the indicated time followingadministration of rebastinib (IP injection of 10 mg/kg, IP injection of50 mg/kg, IM injection of 10 mg/kg, or IM injection of 50 mg/kg). Plasmaconcentrations of rebastinib were determined by LC-MS/MS.

TABLE 2 Dose Dose Level t_(1/2) t_(max) C_(max) AUC_(last) AUC_(∞)MRT_(∞) Route (mg/kg) (hr) (hr) (ng/mL) (hr*ng/mL) (hr*ng/mL) (hr) IP 102.12 2 23683 162488 162568 4.46 50 1.90 2 81633 651387 651534 4.73 IM 105.59 2 8203 93540 98469 7.83 50 8.10 4 15103 222518 256486 11.8 PlasmaPK parameters. t_(1/2): half-life; t_(max): time to maximumconcentration; C_(max): maximum concentration; AUC_(last): area underthe curve from 0 to 24 hours; AUC_(∞): area under the curve to infinity;MRT_(∞): mean residence time to infinity; N = 6

Terminal brain and muscle samples were collected at 1 hour and 24 hoursafter intraperitoneal or intramuscular dose. Uninjected muscle exposurewas significantly higher (up to 1336 ng/g by intraperitonealadministration or 157 ng/g by intramuscular administration) than brainexposure (up to 441 ng/g by intraperitoneal administration or 351 ng/gby intramuscular administration). Exposure of the injected muscle(gastrocnemius) after intramuscular dosing remained high after 24 hours(1441667 ng/g), however brain and contralateral muscle exposure remainedlow in comparison.

FIGS. 31A and 31B provide mean brain and muscle rebastinibconcentration-time profile following a single administration ofrebastinib by either intraperitoneal (IP) or intramuscular injection(IM). FIG. 31A Brain was collected at the indicated time followingadministration of rebastinib (IP injection of 10 mg/kg, IP injection of50 mg/kg, IM injection of 10 mg/kg, or IM injection of 50 mg/kg). Brainconcentrations of rebastinib were determined by LC-MS/MS. Brainconcentration of rebastinib 24 hours after IM injection at 10 mg/kg wasbelow the Lower Limit of Quantification (LLOQ). FIG. 31B. Gastrocnemiusmuscle was collected at the indicated time following administration ofrebastinib (IP injection of 10 mg/kg, IP injection of 50 mg/kg, IMinjection of 10 mg/kg, or IM injection of 50 mg/kg). For IM injectedanimals, both the injected gastrocnemius muscle and the contralateral(uninjected gastrocnemius)) muscle were collected. Muscle concentrationsof rebastinib were determined by LC-MSIMS. Concentrations are shown asmean with SD, N=6

Example 10—Mechanism of Action Study

GBC0905 does not modify the methylation levels of D4Z4 array inFSHD-affected myotubes. Facioscapulohumeral muscular dystrophy (FSHD) islinked to hypomethylation of the D4Z4 macrosatellite repeat array in thesubtelomere region of chromosome 4 at 4q35 and the associated epigeneticderepression of DUX4. (Himeda, C. et al. (2015); Antioxid Redox Signal22(16): 1463-1482.). To examine the mechanism of action of GBC0905 ininhibiting DUX4 expression, we started by testing whether GBC0905affects the methylation levels of the D4Z4 array. Human embryonic stemcell (hESC)-derived healthy (Genea015) or FSHD-affected (Genea049)myoblasts were cultured and differentiated into myotubes. Their DNAmethylation levels at the 4qA and D4Z4 regions on chromosome 4 wereassessed through bisulfite sequencing analysis. (Jones, T. I., et al.(2015) Clin Epigenetics 7:37). Correlating with the disease phenotype,the DNA methylation levels of the FSHD-affected myotubes at 4qA or D4Z4regions were significantly lower than that of the healthy myotubes(FIGS. 32A and 32B—DNA methylation levels in hESC-derived myotubes atthe 4qA and D4Z4 regions on chromosome 4 correlate with FHSD disease).No statistically significant effect. of GBC090S treatment was observedin the DNA methylation levels at 4qA or D4Z4 regions of FHSD-affectedmyotubes at any of the tested concentrations (FIGS. 33A and 33B). Thus,GBC0905 does not silence DUX4 expression through increasing themethylation levels of D4Z4 array.

Healthy (Genea015) or FSHD-affected (Genea049) MSC-derived myoblastswere cultured in Myoblast Media (Genea Biocells) while performing mediachanges every other day. When cells reached confluence, the medium wasswitched to Myottibe Medium (Genea Biocells) without any further mediachanges On myotube day 3, cells were trypsinized and cell pellets wereprepared for bisulfite sequencing analysis. Genomic DNA was isolatedfrom cell pellets using QIAamp DNA Blood Mini Kit (Qiagen) and bisultiteconverted using the EpiTect Kit (Qiagen). The 4qA and D4Z4 regions wereamplified and cloned into the pCR2.1 TOPO vector. The 4qA or D4Z4containing plasmids were transformed into TOP10 chemically competent Ecoli and selected for kanamycin resistance. Sequencing of kanamycinresistant colonies was completed by Sequegen and methylation analysiswas performed using Bisulfite Sequencing DNA Methylation Analysis(BISMA) online software.

FIG. 32A shows bisulfite sequencing analysis of the 4qA and D4Z4 regionsof myotubes derived from unaffected (Genea015, top row) andFSHD-affected (Cienea049, bottom row) subjects. 4q .A bisulfitesequencing assay analyzed 56 CpGs in the distal D4Z4 repeat on40-containing chromosomes and D4Z4 assay analyzed 59 CpGs upstream ofthe DUX4 open reading frame. Each independent chromosome assayed isrepresented by a row with each CpG represented by a box (dark grey boxesindicating methylation, light grey boxes indicating lack of methylation,and empty boxes indicating lack of a CpG detected at that site). FIG.32B shows quantification of the DNA methylation levels at 4qA or D4Z4regions in myotubes derived from hESCs of healthy unaffected andFSHD-affected subjects. *P≤0.05, student's t-test.

FIGS. 33A and 33B show GBC0905 does not modify DNA methylation levels inFHSD-affected myotubes at the 4qA or D4Z4 regions of chromosome 4.

FSHD-affected. (Genea049) embryonic stem cell-derived myoblasts werecultured in Myoblast Media (Genea Biocells) while performing mediachanges every other day. When cells reached confluence, the medium wasswitched to Myotlibe Medium (Genea. Biocells) without any further mediachanges. During myotube formation, cells were treated with DMSO vehicleor 3 concentrations (10 nM, 100 nM or 1 μM) of GBC0905. On myotube day3, myotubes were trypsinized and cell pellets were prepared forbisulfite sequencing analysis. Refer to the FIG. 1 legend for additionaldetails.

Quantification of bisulfite sequencing results of the DNA methylationlevels at 4qA (FIG. 33A) or (FIG. 33B) D4Z4 regions of FSHTD-affectedmyotubes treated with DMSO or GBC0905 at different concentrations.

Knockdown of GBC0905 target kinases leads to DUX4 repression inFSHD-affected myotubes.

Previously GBC0905 was reported to possibly be an inhibitor of multiplekinases, such as SRC family kinases, ABLs, and TIE2. (Chan, W. W., etal. (2011) Cancer Cell 19(4): 556-568; and Harney, A. S., et al. (2017).Mol Cancer Ther 16(11): 2486-2501) A list of 51 potential GBC0905targets was generated. A library of siRNAs against each of these GBC0905targets were delivered to patient biopsy-derived primary myoblasts toidentify the potential targets through which GBC0905 inhibits DUX4 inFSHD-affectcd myotubes. Examination of DUX4 expression levels at myotubestage revealed that knockdown of multiple previously reported GBC0905targets, including SRC and PRKDC, significantly reduced the expressionof DUX4 and also H3.X/Y, primate-specific histones and a cell stressmarker (FIG. 34A). In addition, knockdown of SRC or PRKDC did net leadto cell toxicity or negatively affect myotube formation (FIG. 34B).RT-PCR analysis of PRKDC and SRC mRNA levels 2.5 days post-transfectionverified the significant and specific knockdown of PRKDC and SRC inprimary myotubes transfected siPRKDC or siSRC (FIG. 35).

Patient biopsy-derived primary myoblasts were derived from the quadricepbiopsies of FSHD patients and were obtained from the University ofRochester FSHD Biorepository. Cells were seeded to a collagen-I coatedplate in primary myoblast medium. Medium was changed every other dayuntil cells reached 80% confluence followed by a switch to primarymyotube medium. Control siRNA (scramble (SCR), siGAPDH, siDUX4,siDUX4-2) or siRNAs against GBC0905 targets were transfected withDharmaFECT 1 at a final concentration of 25 nM. After 2.5 days ofmyotube formation, the cells were fixed and analyzed byimmunocytochcmistry and high-content imaging for DUX4, H3.X/Y, MyosinHeavy Chain and nuclei.

FIG. 34 shows quantification results of the expression levels of DUX4(FIG. 34A) and H3.X/Y or myosin heavy chain and ruclear areas (FIG. 34B)in patient biopsy-derived primary myotubes 2.5 days after siRNAtransfection *P≤0.05, ** P≤0.01, ***P≤0.001, ****P≤0.0001, one-way ANOVAcompared to scramble siRNA (SCR)-treated group.

Patient biopsy-derived primary myoblasts were seeded to a collagen-Icoated plate in primary myoblast medium Medium was changed every otherday until cells reached 80% confluence followed by a switch to primarymvotube medium. Control siRNA (siScramble) or siRNAs against PRKDC andSRC were transfected with DharmaFECT 1 at a final concentration of 25nM. After 2.5 days of myotube formation, the cells were lysed withbuffer RLT followed by RNA isolation with RNeasy Plus Mini Kit (Qiagen)500 ng of RNA was used for cDNA synthesis with Superscript IIIfirst-strand synthesis system for RT-PCR (Invitrogen) and both randomhexamers and oligo(dT)₂₀ primers. RT-PCR was performed using TaqMan™Fast Advanced Master Mix (Applied Biosystems). Reactions were analyzedupon a QuantStudio 3 Real-Time PCR machine using the following cycleconditions: 50° C. for 2 minutes, 95° C. for 2 minutes, followed by 40cycles at 95° C. for 15 seconds, 60° C. for 1 minute. Results werenormalized against GAPPH expression.

Normalized expression levels of PRKDC (FIG. 35A) and SRC (FIG. 35B) inpatient-derived primary myotubes transcted with scramble siRNAs, siPRKDCor siSRC. *** P≤0.001, ****P≤0.0001, one-way ANOVA compared to scramblesiRNA-treated group. Combined knockdown of GBC0905 target kinases PRKDCand SRC appears to inhibit DUX4 expression synergistically without celltoxicity or myogenic inhibition effects in FSHD-affected myotubes (FIG.36),

GBC0905 Decreases the Activity Levels of PRKDC and SRC in FSHD-AffectedMyocytes

PRKDC and SRC mRNA levels and kinase activity levels were examined toverily the previously described inhibitory effects of GBC0905 on PRKDCand SRC. First, to understand whether GBC0905 inhibits PRKDC or SRC atthe transcription level, RT-PCR was performed on vehicle or GBC0905treated patient biopsy-derived primary myotubes. No significantdifference was observed in the expression levels of PRKDC or SRC betweenvehicle and GBC0905 treated myotubes (FIG. 37A and FIG. 37B). The kinaseactivity levels of PRKDC and SRC were then assessed throughimmunofluorescence stain of phosphorylated PRKDC²⁶⁰⁹ and phosphorylatedSRC⁴¹⁶ in vehicle or GBC0905 treated primary cells. The intensitydistribution of nuclear phosphorylated PRKDC²⁶⁰⁹ and SRC⁴¹⁶ demonstratedthat GBC0905 led to a significant shift towards lower intensity levels,indicating that GBC0905 inhibits PRKDC and SRC activities inFSHD-affected myocytes (FIG. 38A and FIG. 38B). Together with theevidence that knockdown of PRKDC and SRC led to reduced levels of DUX4expression, we hypothesize that GBC0905 repress DUX4 expression inFSFID-affected myotubes via inhibiting PRKDC and SRC activities

Patient biopsy-derived primary myoblasts were seeded to a collagen-Icoated plate in primary rnyoblast medium. Medium was changed every otherday until cells reached 80% confluence followed by a switch to primarymyotube medium. Cells were treated with vehicle control DMSO or CBC0905at 10 nm, 50 nM, lot) nM, 500 nM or 1 μM. After 2.5 days of myotubeformation, the cells were lysed with buffer RLT followed by RNAisolation with RNeasy Plus Mini Kit (Qiagen). 500 ng of RNA was used forcDNA synthesis with SuperScript III first-strand synthesis system forRT-PCR (Invitrogen) and both random hexamers and oligo(dT)₂₀ primers.RT-PCR was performed using TagMan™ Fast Advanced Master Mix (AppliedBiosystems). Reactions were analyzed upon a QuantStudio 3 Real-Time PCRmachine using the following cycle conditions: 50° C. for 2 minutes, 95°C. for 2 minutes, followed by 40 cycles at 95° C. for 15 seconds, 60° C.for 1 minute, Results were normalized against GAPDH expression.

Normalized expression levels of PRKDC (FIG. 37A) and SRC (FIG. 37B) inpatient-derived primary myotubes treated with DMSO or GBC0905 atdifferent concentrations.

Patient biopsy-derived primary myoblasts were seeded to a collagen-Icoated plate in primary myoblast medium. Medium was changed every otherday until cells reached 80% confluence followed by a switch to primarymyotube medium. Cells were treated with vehicle control DMSO or GBC0905at 100 nM or 500 nM, After 1 hour of compound treatment, the cells werefixed and analyzed by immunocytochemistry and high-content imaging foractive. PRKDC (phosphorylated PRKDC²⁶⁰⁹), active SRC (phosphorylatedSRC⁴¹⁶), and nuclei.

Histograms of intensity distribution of nuclear phosphorylated PRKDC²⁶⁰⁹(FIG. 38A) and nuclear phosphorylated SRC⁴¹⁶ (FIG. 38B) in patientbiopsy-derived primary myocytes treated with vehicle or 100/500 nM ofGBC0905 for 1 hour.

1. A method for modulating DUX4 activity in a subject in need thereofcomprising administering to the subject in need thereof a compositioncomprising a compound, or a pharmaceutically acceptable salt thereof,.having the structure of Formula (III):

wherein Ar is phenyl or 5- or 6-membered heteroaryl; each R¹ isindependently hydrogen, halogen, —CN, —OH, —OR²⁰, —SH, —SR²⁰, —NO₂,——NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰, —S(═O)R²⁰, —S(═O)₂NR²¹R²¹,—C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —OC(═O)OR²¹, —C(═O)NR²¹R²¹,—OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹, —NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹,unsubstituted or substituted C₁-C₆ alkyl, unsubstituted or substitutedC₂-C₆ alkenyl, unsubstituted or substituted C₂-C₆ alkynyl, unsubstitutedor substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted—C₁-C₆-alkylene-cycloalkyl, unsubstituted or substituted—C₁-C₆-alkylene-heterocycloalkyl, unsubstituted or substituted—C₁-C₆-alkylene-aryl, or unsubstituted or substituted—C₁-C₆-alkylene-heteroaryl; n is 0-5; L¹ is absent or*—(CR^(a)R^(b))—C(═O)—, wherein * denotes attachment point to thecarbonyl carbon; R^(a) and R^(b) are independently selected fromhydrogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl; or R^(a) and R^(b) are takentogether with the carbon to which they are attached to form a 3-, 4-,5-, or 6-membered cycloalkyl or a 3-, 4-, 5-, or 6-memberedheterocycloalkyl; each R² is independently hydrogen, halogen, —CN, —OH,—OR²⁰, —NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹, —C(═O)NR²¹R²¹,—NR²¹C(═O)R²⁰, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; or two R² on adjacentatoms are taken together with the atoms to which they are attached toform an unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substituted aryl, orunsubstituted or substituted heteroaryl; m is 0-4; L² is absent, —O—,—O—(C₁-C₄ alkylene)-, or —NR^(c)—C(═O)—; each R^(c) is independentlyselected from hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; R³ isunsubstituted or substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; wherein when R³ is substituted, it issubstituted by 1-3 R⁴; each R⁴ is independently hydrogen, halogen, —CN,—OH, —OR²⁰, —SH, —SR²⁰, —NO₂, —NR²¹R²¹, —S(═O)₂R²⁰, —NR²¹S(═O)₂R²⁰,—S(═O)R²⁰, —S(═O)₂NR²¹R²¹, —C(═O)R²⁰, —OC(═O)R²⁰, —C(═O)OR²¹,—OC(═O)OR²¹, —C(═O)NR²¹R²¹, —OC(═O)NR²¹R²¹, —NR²¹C(═O)NR²¹R²¹,—NR²¹C(═O)R²⁰, —NR²¹C(═O)OR²¹, unsubstituted or substituted C₁-C₆ alkyl,unsubstituted or substituted C₂-C₆ alkenyl, unsubstituted or substitutedC₂-C₆ alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted heterocycloalkyl, unsubstituted or substituted aryl, orunsubstituted or substituted heteroaryl; each R²⁰ is independentlyselected from unsubstituted or substituted C₁-C₆alkyl, unsubstituted orsubstituted C₂-C₆ alkenyl, unsubstituted or substituted C₂-C₆ alkynyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; each R²¹ is independently selected fromhydrogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted orsubstituted C₁-C₆alkenyl, unsubstituted or substituted C₁-C₆ alkynyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedheterocycloalkyl, unsubstituted or substituted aryl, or unsubstituted orsubstituted heteroaryl; or two R²¹ on the same N atom are taken togetherwith the N atom to which they are attached to form an unsubstituted orsubstituted N-containing heterocycle; wherein when any R¹, R², R⁴, R²⁰,or R²¹ is substituted, substituents on the R¹, R², R⁴, R²⁰, or R²¹ areindependently selected at each occurrence from halogen, —CN, —NO₂,—OR²², —CO₂R²², —C(═O)R²³, —C(═O)NR²²R²², —NR²²R²², —NR²²C(═O)R²³,—NR²²C(═O)OR²², —SR²², —S(═O)R²³, —SO₂R²³, —SO₂NR²²NR²², C₁-C₆ alkyl,C₁-C₆ haloalkyl, monocyclic cycloalkyl, monocyclic heterocycloalkyl,phenyl, benzyl, 5-membered heteroaryl, and 6-membered heteroaryl; or twosubstituents on the same carbon atom are taken together to form a C═O orC═S; each R²² is independently selected from hydrogen, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, phenyl, benzyl, 5-membered heteroaryl, and 6-memberedheteroaryl; or two R²² groups are taken together with the N atom towhich they are attached to form a N-containing heterocycle; and each R²³is independently selected from C₁-C₆alkyl, C₃-C₆ cycloalkyl, phenyl,benzyl, 5-membered heteroaryl, and 6-membered heteroaryl.
 2. The methodof claim 1, wherein the modulating DUX4 activity comprises reducingexpression of DUX4.
 3. The method of claim 1, wherein DUX4 expression ismonitored by monitoring DUX4 mRNA expression, DUX4 protein expression,or both DUX4 mRNA expression and DUX4 protein expression.
 4. The methodof claim 1, wherein the DUX4 target gene is one or more genes selectedfrom the group consisting of CCNA1, KHDC1L, LEUTX, M8D3L2, PRAMEF2,PRAMEF6, SPRYD5, TRIM43, TRIM49, ZNF296, and ZSCAN4.
 5. The method ofclaim 1, wherein the compound comprises rebastinib,4-(4-(3-(3-(tert-butyl)-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureido)-2-methylphenoxy)-N-methylpicolinamide,or4-(4-(3-(3-(tert-butyl)-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)ureido)-3-fluorophenoxy)-N-methylpicolinamide.6. A method for modulating DUX4 activity in a subject in need thereofcomprising administering to the subject in need thereof a compositioncomprising a compound, or a pharmaceutically acceptable salt thereof,having the structure of Formula (I):

wherein E1 is phenyl, and wherein the E1 ring is substituted with one tothree R¹⁶ moieties; wherein A is selected from the group consisting ofimidazolyl, and pyrazolyl; G1 is a heteroaryl taken from the groupconsisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, andpyrimidinyl; G4 is a heterocyclyl taken from the groqj consisting ofoxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl,dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinylS-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl,diazepinyl, tropanyl, and homotropanyl; A ring is substituted at anysubstitutable position with one A1 moiety, wherein A1 is selected fromthe group consisting of: A ring is substituted at any substitutableposition with one Al moiety. wherein Al is selected from the groupconsisting

and wherein the symbol (**) is the point of attachment to the A ring offormula I; and wherein — indicates either a saturated or unsaturatedbond; the A ring is optionally substituted with one or more R2 moieties;X2 is a direct bond wherein E1 is directly linked to the NR3 group offormula I; X3 is —O—; V, V1, and V2 are each independently O orrepresent two hydrogens attached to the methylene carbon to which the V,V1, or V2 is attached; each Z3 is independently and individuallyselected from the group consisting of H, C1-C6alkyl, branchedC3-C7alkyl, C3-C8carbocyclyl, halogen, fluoroC1-C6alkyl wherein thealkyl moiety can be partially or fully fluorinated, cyano, hydroxyl,methoxy, oxo, (R3)₂NC(O)—, (R4)₂NC(O)—, —N(R4)C(O)R8, (R3)₂NSO₂—,(R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —(CH₂)N(R3)₂, —(CH₂)_(q)N(R4)₂,—O(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)O—C1-C6alkyl,—N(R3)(CH2)_(q)O—C1-C6alkyl,—N(R3)(CH₂)_(q)N(R4)₂, —O(CH2)_(q)R5, —N(R3)(CH₂)_(q)R5, —C(O)R5,—C(O)R8, and nitro; in the event that Z3 contains an alkyl or alkylenemoiety, such moieties may be further substituted with one or moreC1-C6alkyls; each Z4 is independently and individually selected from thegroup consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl,C1-C6alkoxyC₂-C₆alkyl, (R4)₂N—C₂-C₆alkyl,(R4)₂N—C₂-C6alkylN(R4)-C₂-C₆alkyl, (R4)₂N—C₂-C₆alkyl-O—C₂-C₆alkyl,(R4)₂NC(O)—C1-C6alkyl, carboxyC1-C6alkyl-,C1-C6alkoxycarbonylC1-C6alkyl-, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)—,—SO₂R8, —C(O)R8, —(CH₂)_(n)G1, —(CH₂)_(n)G4, —(CH₂)_(q)O(CH₂)_(n)G1,—(CH₂)_(q)O(CH₂)_(n)G4, —(CH₂)_(q)N(R3)(CH₂)_(n)G1,—(CH₂)_(q)N(R3)(CH₂)_(n)G4, —(CH₂)_(q)NHC(O)(CH₂)_(n)R5,—(CH₂)_(q)C(O)NH(CH₂)_(q)R₅, —(CH₂)_(q)C(O)R5, —(CH₂)_(q)OC(O)R5,—(CH₂)_(q)R5, —(CH₂)_(q)NR4(CH₂)_(q)R5, and —(CH₂)_(q)O(CH₂)_(q)R5; inthe event that Z4 contains an alkyl or alkylene moiety, such moietiesmay be further substituted with one or more C1-C6alkyls; each Z6 isindependently and individually selected from the group consisting of H,C1-C6alkyl, branched C3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl,hydroxyC₂-C₆ branched alkyl, C1-C6alkoxy, C1-C6alkoxyC1-C6alkyl-,C1-C6alkoxyC₂-C₆ branched alkyl-, C2-C6 branched alkoxy-,C1-C6alkylthio-, (R3)₂N—, —N(R3)C(O)R8, (R4)₂N—, —R5, —N(R4)C(O)R8,—N(R3)SO₂R6, —C(O)N(R3)₂, —C(O)N(R4)₂, —C(O)R5, —SO₂NH(R4), halogen,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,cyano, fluoroC1-C6alkoxy wherein the alkyl is fully or partiallyfluorinated, —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)N(R4)₂,—O(CH₂)_(q)O—C1-C6alkyl, —O(CH₂)_(q)N(R4)₂, —N(R3)(CH₂)_(q)O—C1-C6alkyl,—N(R₃)(CH₂)_(q)N(R4)₂, —O(CH₂)_(q)R5, N(R3)(CH₂)_(q)R₅, —(NR3)_(r)R17,—(O)_(r)R17, —(S)_(r)R17, —(CH₂)_(n)R17, —R17, —(CH₂)_(n)G1,—(CH₂)_(n)G4, —(CH₂)_(n)O(CH₂)_(n)G1, —(CH₂)_(n)O(CH₂)_(n)G4,—(CH₂)_(n)N(R3)(CH₂)_(n)G1, and —(CH₂)_(n)N(R3)(CH2)_(n)G4; each R2 isselected from the group consisting of Z3-substituted aryl,Z3-substituted G1-, Z3-substituted G4-, C1-C6alkyl, branched C3-C8alkyl,R19 substituted C3-C8cycloalkyl fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, cyano, C1-C6alkoxy, andfluoroC1-C6alkoxy wherein the alkyl group is fully or partiallyfluorinated; wherein each R3 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, branched C3-C7alkyl,C3-C7-cartocyclyl, and Z3-substituted phenyl; each R4 is independentlyand individually selected from the group consisting of H, C1-C6alkyl,hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-,branched C3-C7alkyl-, branched hydroxyC1-C6alkyl-, branchedC1-C6alkoxyC1-C6alkyl-, branched dihydroxyC₂-C₆alkyl-, —(CH₂)_(p)N(R7)₂,—(CH₂)_(p)R5, —(CH₂)_(p)C(O)N(R7)₂, —(CH₂)_(n)C(O)R5,—(CH₂)_(n)C(O)OR3,C3-C7-carbocyclyl, hydroxyl substituted C3-C7-carbocyclyl-, alkoxysubstituted C3-C7-carbocyclyl-, dihydroxyl substitutedC3-C7-carbocyclyl-, and —(CH₂)_(n)R17; each R5 is independently andindividually selected from the group consisting of

and wherein the symbol (##) is the point of attachment of the R5 moiety;each R6 is independently and individually selected from the groupconsisting of C1-C6alkyl, branched C3-C7alkyl, C3-C7-carbocyclyl,phenyl, G1, and G4; each R7 is independently and individually selectedfrom the group consisting of H, C1-C6alkyl, hydroxyC₂-C₆alkyl-,dihydroxyC₂-C₆alkyl-, C₂-C₆alkoxyC₂-C₆alkyl-, branched C3-C7alkyl-,branched hydroxyC₂-C₆ alkyl-, branched C₂-C₆alkoxyC2-C6alkyl-, brancheddihydroxyC₂-C₆alkyl-, —(CH₂)_(q)R5, —(CH₂)_(n)C(O)R5, —(CH₂)_(n)C(O)OR3,C3-C7-carbocyclyl,hydroxyl substituted C3-C7-carbocyclyl-, alkoxysubstituted C3-C7-carbocyclyl-, dihydroxy substituted C3-C7-carbocyclyl,and —(CH₂)_(n)R17; each R8 is independently and individually selectedfrom the group consisting of C1-C6alkyl, branched C3-C7alkyl,fluoroC1-C6alkyl wherein the alkyl moiety is partially or fullyfluorinated, C3-C7-carbocyclyl, phenyl-, phenylC1-C6alkyl-, G1,G1-C1-C6alkyl-, G4, G4-C1-C6alkyl-, OH, C1-C6alkoxy, N(R3)₂, N(R4)₂, andR5; each R9 is independently and individually selected from the groupconsisting of H, F, C1-C6alkyl, branched C3-C7alkyl, C3-C7-carbocyclyl,phenyl, phenyl-C1-C6alkyl-, —(CH₂)_(n)G1, and —(CH₂)_(n)G4; each R10 isindependently and individually selected from the group consisting ofCO₂H,CO₂C1-C6alkyl, —C(O)N(R4)₂, OH, C1-C6alkoxy, and —N(R4)₂; each R14is independently and respectively selected from the group consisting ofH, C1-C6alkyl, branched C3-C6alkyl, and C3-C7-carbocyclyl; R16 isindependently and individually selected from the group consisting offluorine and methyl; each R17 is taken from the group comprising phenyl,naphthyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl,isothiazolyl, imdazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl,triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, triazinyl, oxetanyl,azctadinyl, tetrahydrofuranyl, oxazolinyl, oxazolidinyl, pyranyl,thiopyranyl, tetrahydropyranyl, dioxalinyl, azepinyl, oxepinyl, anddiazepinyl; wherein R17 can be optionally substituted with an R3substituent, R19 is H or C1-C6 alkyl; n is 0-6, p is 1-4, q is 2-6; r is0 or 1; t is 1-3, and v is 1 or
 2. 7. The method of claim 6, wherein themodulating DUX4 activity comprises reducing expression of DUX4.
 8. Themethod of claim 7, wherein the reduction of DUX4 expression occurs atthe mRNA level or at the protein level.
 9. The method of claim 6,wherein DUX4 expression is monitored by monitoring DUX4 mRNA expression,DUX4 protein expression, or both DUX4 mRNA expression and DUX4 proteinexpression.
 10. The method of claim 6, wherein the DUX4 target gene isone or more genes selected from the group consisting of CCNA1, KHDC1L,LEUTX, M8D3L2, PRAMEF2, PRAMEF6, SPRYD5, TRIM43, TRIM49, ZNF296, andZSCAN4.
 11. The method of claim 6, further comprising conducting amuscle or tissue biopsy on the subject in need thereof.
 12. The methodof claim 6, further comprising monitoring a level of the compound in thesubject over time.
 13. The method of claim 6, wherein the compoundcomprises rebastinib,4-(4-(3-(3-(tert-butyl)-1-(quinolin-6-yl)-1H-pyrazol-5-yl)ureido)-2-methylphenoxy)-N-methylpicolinamide,or4-(4-(3-(3-(tert-butyl)-1-(1H-indazol-5-yl)-1H-pyrazol-5-yl)ureido)-3-fluorophenoxy)-N-methylpicolinamide.14. The method of claim 6, wherein prior to, following or both prior toand following administration of the compound, the method furthercomprises monitoring one or more of the following in the subject in needthereof: one or more markers of muscle injury, one or more muscleenzymes, creatinine kinase, aldolase, DUX4, or any combination thereof.15. A method for modulating DUX4 activity in a subject in need thereofcomprising administering to the subject in need thereof a compositioncomprising a compound, or a pharmaceuticatly acceptable salt thereof,having, the structure of Formula (II):

wherein A is pyrazolyl.